Endoplasmic reticulum morphology regulation by RTN4 modulates neuronal regeneration by curbing luminal transport.

Cell functions rely on intracellular transport systems distributing bioactive molecules with high spatiotemporal accuracy. The endoplasmic reticulum (ER) tubular network constitutes a system for delivering luminal solutes, including Ca2+, across the cell periphery. How the ER structure enables this nanofluidic transport system is unclear. Here, we show that ER membrane-localized reticulon 4 (RTN4/Nogo) is sufficient to impose neurite outgrowth inhibition in human cortical neurons while acting as an ER morphoregulator. Improving ER transport visualization methodologies combined with optogenetic Ca2+ dynamics imaging and in silico modeling, we observed that ER luminal transport is modulated by ER tubule narrowing and dilation, proportional to the amount of RTN4. Excess RTN4 limited ER luminal transport and Ca2+ release, while RTN4 elimination reversed the effects. The described morphoregulatory effect of RTN4 defines the capacity of the ER for peripheral Ca2+ delivery for physiological releases and thus may constitute a mechanism for controlling the (re)generation of neurites.

An Ex-Vivo Study Comparing the Accuracy of the E-Connect S+ and Morita Tri Auto ZX2+ Endodontic Handpieces in Root Canal Length Determination.

INTRODUCTION: This ex vivo study evaluated the accuracy of the Electronic Apex Locator (EAL) and Automatic Apical Stop (AAS) functions of the E-Connect S+ and Morita Tri Auto ZX2+ cordless apex locators in determining patency length. METHODS: Sixty-four human teeth with a single root were randomly allocated into E-connect or Morita groups (n = 32). The canals were accessed and preflared, after which a size 15 K-file was inserted into the canal to the major foramen and recorded as the actual length (AL). Matched measurements were taken using the AAS and EAL functions and visually confirmed with confocal microscopy. The variance between canal length (mm), the persons correlation (ρ) between function and AL, and the accuracy (%) of the canal length relative to the AL (Δmm) between devices and functions were assessed. RESULTS: Regardless of device or function, all measurements were within 1±Δmm and correlated strongly (ρ > 0.97) with the AL. When considering a more stringent clinically acceptable range of 0.5±Δmm from the AL, all devices and functions demonstrated similar accuracy levels (84%-94%). However, at lower tolerance ranges, the E-connect device with the EAL function exhibited the highest accuracy. On average, all devices and functions stopped short of the AL (mean Δmm>0). CONCLUSION: The E-Connect S+ and Morita Tri Auto ZX2+ apex locators provided reliable accuracy in determining the position of the major foramen. These findings demonstrate a high level of reproducibility in canal length measurements using both cordless endodontic handpieces, regardless of whether the EAL or AAS functions were employed.

Inshore and offshore marine migration pathways of Atlantic salmon post-smolts from multiple rivers in Scotland, England, Northern Ireland, and Ireland.

The migratory behavior of Atlantic salmon (Salmo salar) post-smolts in coastal waters is poorly understood. In this collaborative study, 1914 smolts, from 25 rivers, in four countries were tagged with acoustic transmitters during a single seasonal migration. In total, 1105 post-smolts entered the marine study areas and 438 (39.6%) were detected on a network of 414 marine acoustic receivers and an autonomous underwater vehicle. Migration pathways (defined as the shortest distance between two detections) of up to 575 km and over 100 days at sea were described for all 25 populations. Post-smolts from different rivers, as well as individuals from the same river, used different pathways in coastal waters. Although difficult to generalize to all rivers, at least during the year of this study, no tagged post-smolts from rivers draining into the Irish Sea were detected entering the areas of sea between the Hebrides and mainland Scotland, which is associated with a high density of finfish aquaculture. An important outcome of this study is that a high proportion of post-smolts crossed through multiple legislative jurisdictions and boundaries during their migration. This study provides the basis for spatially explicit assessment of the impact risk of coastal pressures on salmon during their first migration to sea.

Luminal transport through intact endoplasmic reticulum limits the magnitude of localized Ca2+ signals.

The endoplasmic reticulum (ER) forms an interconnected network of tubules stretching throughout the cell. Understanding how ER functionality relies on its structural organization is crucial for elucidating cellular vulnerability to ER perturbations, which have been implicated in several neuronal pathologies. One of the key functions of the ER is enabling Ca[Formula: see text] signaling by storing large quantities of this ion and releasing it into the cytoplasm in a spatiotemporally controlled manner. Through a combination of physical modeling and live-cell imaging, we demonstrate that alterations in ER shape significantly impact its ability to support efficient local Ca[Formula: see text] releases, due to hindered transport of luminal content within the ER. Our model reveals that rapid Ca[Formula: see text] release necessitates mobile luminal buffer proteins with moderate binding strength, moving through a well-connected network of ER tubules. These findings provide insight into the functional advantages of normal ER architecture, emphasizing its importance as a kinetically efficient intracellular Ca[Formula: see text] delivery system.

Regression of Multiple Intracranial Meningiomas With Cessation of Progesterone Agonist Therapy: A Case Report.

In this case report, we discuss a patient who experienced spontaneous regression of multiple intracranial meningiomas that were treated conservatively for 5 years after cessation of megestrol acetate, an exogenous progestin. In addition, we discuss the previous literature describing the relationship between exogenous progesterone medications and meningioma growth. This case, along with others reported, implies that cessation of progesterone therapy, when feasible, may alter the natural history of meningioma growth and thus impact treatment decisions.

Colonization, diversity, and seasonality of fishes at pelagic fish aggregating devices.

The pelagic zone of the ocean can be a challenging environment in which to conduct research and as a result we lack the robust baseline abundance and diversity data, compared to what is available in more accessible coastal habitats, to be able to track changes or stressors to the biota in this environment. Many large-scale fisheries target pelagic fish, and much of the information available on these species is based on fisheries-dependent data that may be biased towards hotspots and commercially valuable fishes. Here, a long-term video and visual fish survey was conducted on two subsurface moored fish aggregating devices (FADs) in the pelagic waters of the central Bahamas to determine the feasibility of using moored pelagic FADs as tools for collecting fish abundance and diversity data. A wide range of species was documented, including large migratory fish that are the focus of commercial and recreational fisheries, and smaller often overlooked species on which little abundance or seasonality information exists. We found that FADs colonize quickly and reach a peak stable (albeit seasonally cyclical) abundance and diversity within the first several months after deployment. Species richness was higher in video surveys, but abundance was higher in visual surveys, except for sharks. Our results highlight the need to tailor survey methods to fit the context and study objective, and provide further evidence for the importance of fisheries-independent data in monitoring pelagic species.

Migration patterns and navigation cues of Atlantic salmon post-smolts migrating from 12 rivers through the coastal zones around the Irish Sea.

The freshwater phase of the first seaward migration of juvenile Atlantic salmon (Salmo salar) is relatively well understood when compared with our understanding of the marine phase of their migration. In 2021, 1008 wild and 60 ranched Atlantic salmon smolts were tagged with acoustic transmitters in 12 rivers in England, Scotland, Northern Ireland and Ireland. Large marine receiver arrays were deployed in the Irish Sea at two locations: at the transition of the Irish Sea into the North Atlantic between Ireland and Scotland, and between southern Scotland and Northern Ireland, to examine the early phase of the marine migration of Atlantic salmon smolts. After leaving their natal rivers' post-smolt migration through the Irish Sea was rapid with minimum speeds ranging from 14.03 to 38.56 km.day-1 for Atlantic salmon smolts that entered the Irish Sea directly from their natal river, to 9.69-39.94 km.day-1 for Atlantic salmon smolts that entered the Irish Sea directly from their natal estuary. Population minimum migration success through the study area was strongly correlated with the distance of travel, populations further away from the point of entry to the open North Atlantic exhibited lower migration success. Post-smolts from different populations experienced different water temperatures on entering the North Atlantic. This was largely driven by the timing of their migration and may have significant consequences for feeding and ultimately survivorship. The influence of water currents on post-smolt movement was investigated using data from previously constructed numerical hydrodynamic models. Modeled water current data in the northern Irish Sea showed that post-smolts had a strong preference for migrating when the current direction was at around 283° (west-north-west) but did not migrate when exposed to strong currents in other directions. This is the most favorable direction for onward passage from the Irish Sea to the continental shelf edge current, a known accumulation point for migrating post-smolts. These results strongly indicate that post-smolts migrating through the coastal marine environment are: (1) not simply migrating by current following (2) engage in active directional swimming (3) have an intrinsic sense of their migration direction and (4) can use cues other than water current direction to orientate during this part of their migration.

Knowledge About the Source of Emotion Predicts Emotion-Regulation Attempts, Strategies, and Perceived Emotion-Regulation Success.

People's ability to regulate emotions is crucial to healthy emotional functioning. One overlooked aspect in emotion-regulation research is that knowledge about the source of emotions can vary across situations and individuals, which could impact people's ability to regulate emotion. Using ecological momentary assessments (N = 396; 7 days; 5,466 observations), we measured adults' degree of knowledge about the source of their negative emotions. We used language processing to show that higher reported knowledge led to more concrete written descriptions of the source. We found that higher knowledge of the source predicted more emotion-regulation attempts; increased the use of emotion-regulation strategies that target the source (cognitive reappraisal, situation modification) versus strategies that do not (distraction, emotional eating); predicted greater perceived success in regulating emotions; and greater well-being. These patterns were evident both within and between persons. Our findings suggest that pinpointing the source of emotions might play an important role in emotion regulation.

2023 International Olympic Committee's (IOC) consensus statement on Relative Energy Deficiency in Sport (REDs).

Relative Energy Deficiency in Sport (REDs) was first introduced in 2014 by the International Olympic Committee's expert writing panel, identifying a syndrome of deleterious health and performance outcomes experienced by female and male athletes exposed to low energy availability (LEA; inadequate energy intake in relation to exercise energy expenditure). Since the 2018 REDs consensus, there have been >170 original research publications advancing the field of REDs science, including emerging data demonstrating the growing role of low carbohydrate availability, further evidence of the interplay between mental health and REDs and more data elucidating the impact of LEA in males. Our knowledge of REDs signs and symptoms has resulted in updated Health and Performance Conceptual Models and the development of a novel Physiological Model. This Physiological Model is designed to demonstrate the complexity of either problematic or adaptable LEA exposure, coupled with individual moderating factors, leading to changes in health and performance outcomes. Guidelines for safe and effective body composition assessment to help prevent REDs are also outlined. A new REDs Clinical Assessment Tool-Version 2 is introduced to facilitate the detection and clinical diagnosis of REDs based on accumulated severity and risk stratification, with associated training and competition recommendations. Prevention and treatment principles of REDs are presented to encourage best practices for sports organisations and clinicians. Finally, methodological best practices for REDs research are outlined to stimulate future high-quality research to address important knowledge gaps.

Predicting the target landscape of kinase inhibitors using 3D convolutional neural networks.

Many therapies in clinical trials are based on single drug-single target relationships. To further extend this concept to multi-target approaches using multi-targeted drugs, we developed a machine learning pipeline to unravel the target landscape of kinase inhibitors. This pipeline, which we call 3D-KINEssence, uses a new type of protein fingerprints (3D FP) based on the structure of kinases generated through a 3D convolutional neural network (3D-CNN). These 3D-CNN kinase fingerprints were matched to molecular Morgan fingerprints to predict the targets of each respective kinase inhibitor based on available bioactivity data. The performance of the pipeline was evaluated on two test sets: a sparse drug-target set where each drug is matched in most cases to a single target and also on a densely-covered drug-target set where each drug is matched to most if not all targets. This latter set is more challenging to train, given its non-exclusive character. Our model's root-mean-square error (RMSE) based on the two datasets was 0.68 and 0.8, respectively. These results indicate that 3D FP can predict the target landscape of kinase inhibitors at around 0.8 log units of bioactivity. Our strategy can be utilized in proteochemometric or chemogenomic workflows by consolidating the target landscape of kinase inhibitors.

Screening of predicted synergistic multi-target therapies in glioblastoma identifies new treatment strategies.

Background: IDH-wildtype glioblastoma (GBM) is a highly malignant primary brain tumor with a median survival of 15 months after standard of care, which highlights the need for improved therapy. Personalized combination therapy has shown to be successful in many other tumor types and could be beneficial for GBM patients. Methods: We performed the largest drug combination screen to date in GBM, using a high-throughput effort where we selected 90 drug combinations for their activity onto 25 patient-derived GBM cultures. 43 drug combinations were selected for interaction analysis based on their monotherapy efficacy and were tested in a short-term (3 days) as well as long-term (18 days) assay. Synergy was assessed using dose-equivalence and multiplicative survival metrics. Results: We observed a consistent synergistic interaction for 15 out of 43 drug combinations on patient-derived GBM cultures. From these combinations, 11 out of 15 drug combinations showed a longitudinal synergistic effect on GBM cultures. The highest synergies were observed in the drug combinations Lapatinib with Thapsigargin and Lapatinib with Obatoclax Mesylate, both targeting epidermal growth factor receptor and affecting the apoptosis pathway. To further elaborate on the apoptosis cascade, we investigated other, more clinically relevant, apoptosis inducers and observed a strong synergistic effect while combining Venetoclax (BCL targeting) and AZD5991 (MCL1 targeting). Conclusions: Overall, we have identified via a high-throughput drug screening several new treatment strategies for GBM. Moreover, an exceptionally strong synergistic interaction was discovered between kinase targeting and apoptosis induction which is suitable for further clinical evaluation as multi-targeted combination therapy.

Prophylactic immunization to Helicobacter pylori infection using spore vectored vaccines.

BACKGROUND: Helicobacter pylori infection remains a major public health threat leading to gastrointestinal illness and increased risk of gastric cancer. Mostly affecting populations in developing countries no vaccines are yet available and the disease is controlled by antimicrobials which, in turn, are driving the emergence of AMR. MATERIALS AND METHODS: We have engineered spores of Bacillus subtilis to display putative H. pylori protective antigens, urease subunit A (UreA) and subunit B (UreB) on the spore surface. Following oral dosing of mice with these spores, we evaluated immunity and colonization in animals challenged with H. pylori. RESULTS: Oral immunization with spores expressing either UreA or UreB showed antigen-specific mucosal responses (fecal sIgA) including seroconversion and hyperimmunity. Following challenge, colonization by H. pylori was significantly reduced by up to 1-log. CONCLUSIONS: This study demonstrates the utility of bacterial spores for mucosal vaccination to H. pylori infection. The heat stability and robustness of Bacillus spores coupled with their existing use as probiotics make them an attractive solution for either protection against H. pylori infection or potentially for therapy and control of active infection.

Gender differences in appointments to pathology department interim chair positions and subsequent advancement to permanent chair positions.

Females are under-represented as departmental chairs in academic medical centers and identifying ways to increase their numbers in this position would be useful. A previous study of women chairs of pathology showed that 35% of permanent chairs had previously been interim chairs, suggesting that the interim position was a common pathway for women to advance to a permanent chair position. We sought to determine whether it might also be true for males and if not, possible reasons for the difference. Between January 2016 and June 2022, the Association of Pathology Chairs identified 50 people who had served as interim pathology department chairs. Males served as interim chairs more often than females (66% vs 34%), but, within this time frame, female interim chairs were more likely to become permanent chairs than males (47% of females compared to 27% of males). To better understand the difference in the rate of advancement from interim to permanent chair, we surveyed the 50 individuals who had served as interim chairs to explore gender differences in backgrounds, reasons for serving as interim chairs and reasons for seeking or not seeking the permanent chair position. No significant gender differences were found except that male interim chairs were older (59.2 years) than female interim chairs (50.4 years). This study affirms that serving as an interim chair is a common pathway for females to become permanent chairs, while it is less so for males, although the reasons for this difference could not be determined.

Minimally Invasive Image-Guided Transgluteal Approach for Resection of a Sciatic Nerve Tumor: A Technical Note.

There are a variety of surgical approaches to lesions around the sciatic notch. Historically, peripheral nerve surgeons prefer an infragluteal approach involving a large incision with reflection of the gluteus maximus to better visualize the operative field. This approach was imperative when lesion localization was imprecise. Comparatively, orthopedic surgeons prefer a muscle-splitting, transgluteal approach to operate on the static structures of the posterior hip. The transgluteal approach is significantly less morbid, allowing for same-day discharge and less extensive rehab given preservation of the gluteal muscle. In this article we describe the use of dynamic ultrasound imaging to localize and aid in the resection of three unique tumors around the sciatic notch using a minimally invasive, tissue-sparing, transgluteal technique. We offer a comprehensive description of the benefits, anatomic considerations, and nuances of using a transgluteal approach for the resection of lesions at the sciatic notch.

HNRNPH1 regulates the neuroprotective cold-shock protein RBM3 expression through poison exon exclusion.

Enhanced expression of the cold-shock protein RNA binding motif 3 (RBM3) is highly neuroprotective both in vitro and in vivo. Whilst upstream signalling pathways leading to RBM3 expression have been described, the precise molecular mechanism of RBM3 cold induction remains elusive. To identify temperature-dependent modulators of RBM3, we performed a genome-wide CRISPR-Cas9 knockout screen using RBM3-reporter human iPSC-derived neurons. We found that RBM3 mRNA and protein levels are robustly regulated by several splicing factors, with heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) being the strongest positive regulator. Splicing analysis revealed that moderate hypothermia significantly represses the inclusion of a poison exon, which, when retained, targets the mRNA for nonsense-mediated decay. Importantly, we show that HNRNPH1 mediates this cold-dependent exon skipping via its thermosensitive interaction with a G-rich motif within the poison exon. Our study provides novel mechanistic insights into the regulation of RBM3 and provides further targets for neuroprotective therapeutic strategies.

Racial and ethnic disparities in the treatment and outcomes for witnessed out-of-hospital cardiac arrest in Connecticut.

BACKGROUND: Racial and ethnic disparities in the treatment and outcomes for witnessed out-of-hospital cardiac arrest (OHCA) in the United States have been previously described. We sought to characterize disparities in pre-hospital care, overall survival, and survival with favorable neurological outcomes following witnessed OHCA in the state of Connecticut. METHODS: We performed a cross-sectional study to compare pre-hospital treatment and outcomes for White versus Black and Hispanic (Minority) OHCA patients submitted from Connecticut to the Cardiac Arrest Registry to Enhance Survival (CARES) between 2013 and 2021. Primary outcomes included bystander CPR use, bystander automated external defibrillator (AED) use with attempted defibrillation, overall survival, and survival with favorable cerebral function. RESULTS: 2,809 patients with witnessed OHCA were analyzed (924 Black or Hispanic; 1885 White). Minorities had lower rates of bystander CPR (31.4% vs 39.1%, P = 0.002) and bystander AED placement with attempted defibrillation (10.5% vs 14.4%, P = 0.004), with lower rates of survival to hospital discharge (10.3% vs 14.8%, P = 0.001) and survival with favorable cerebral function (65.3% vs 80.2%, P = 0.003). Minorities were less likely to receive bystander CPR in communities with median annual household income >$80, 000 (OR, 0.56; 95% CI, 0.33-0.95; P = 0.030) and in integrated neighborhoods (OR, 0.70; 95% CI, 0.52-0.95; P = 0.020). CONCLUSIONS: Black and Hispanic Connecticut patients with witnessed OHCA have lower rates of bystander CPR, attempted AED defibrillation, overall survival, and survival with favorable neurological outcomes compared to White patients. Minorities were less likely to receive bystander CPR in affluent and integrated communities.

The Biochemistry and Effectiveness of Antioxidants in Food, Fruits, and Marine Algae.

It is more effective to maintain good health than to regain it after losing it. This work focuses on the biochemical defense mechanisms against free radicals and their role in building and maintaining antioxidant shields, aiming to show how to balance, as much as possible, the situations in which we are exposed to free radicals. To achieve this aim, foods, fruits, and marine algae with a high antioxidant content should constitute the basis of nutritional elements, since natural products are known to have significantly greater assimilation efficiency. This review also gives the perspective in which the use of antioxidants can extend the life of food products, by protecting them from damage caused by oxidation as well as their use as food additives.

Severity of coeliac disease and clinical management study when using a non-metabolised medication: a phase I pharmacokinetic study.

OBJECTIVE: The non-metabolised antihistamine fexofenadine has oral absorption resulting from transporter activity. Uptake by enterocyte organic anion transporting polypeptides and efflux by an ATP-binding cassette transporter (P-glycoprotein) are primary determinants. Coeliac disease-mediated lesions to the small intestinal mucosa may alter oral absorption of the drug probe, fexofenadine. DESIGN: A phase I, open-label, single-dose, pharmacokinetic study SETTING: London, Ontario, Canada PARTICIPANTS: Patients with coeliac disease (n=41) with positive serology and healthy individuals (n=48). MAIN OUTCOME MEASURES: Patients with coeliac disease-duodenal histology and oral fexofenadine pharmacokinetics within a 3-week period. Healthy individuals-oral fexofenadine pharmacokinetics with water and grapefruit juice. RESULTS: Patients with coeliac disease were stratified by disease severity: Group A (n=15, normal), B+C (n=14, intraepithelial lymphocytosis with/without mild villous blunting) and D (n=12, moderate to severe villous blunting). Patients with coeliac disease in groups A, B+C and D and healthy individuals receiving water had similar fexofenadine AUC0-8 (2038±304, 2259±367, 2128±410, 1954±138 ng.h/mL; p>0.05; mean±SEM) and Cmax (440±73, 513±96, 523±104, 453±32 ng/mL; p>0.05), respectively. These four groups all had higher fexofenadine AUC0-8 (1063±59; p<0.01) and Cmax (253±18; p<0.05) compared with those for healthy individuals receiving grapefruit juice. Coeliac groups had a positive linear trend between disease severity and fexofenadine Tmax (2.0±0.3, 2.7±0.4, 3.1±0.5 hours; p<0.05). CONCLUSIONS: Coeliac disease severity based on duodenal histopathology did not affect oral fexofenadine bioavailability. Increased Tmax suggested absorption distal to the duodenum (jejunum + ileum), where histology seems more normal which may be the key determinant. Patients with coeliac disease may not require consideration for alternative clinical drug management for a number of non-metabolised and transport-mediated medications.