A bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site.

Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity and improve current medications by reducing off-target side effects. However, the lack of structural information on their binding mode impedes rational design. Here we determine the cryo-EM structure of the hD3R:GαOßγ complex bound to the D3R selective bitopic agonist FOB02-04A. Structural, functional and computational analyses provide insights into its binding mode and point to a new TM2-ECL1-TM1 region, which requires the N-terminal ordering of TM1, as a major determinant of subtype selectivity in aminergic GPCRs. This region is underexploited in drug development, expands the established secondary binding pocket in aminergic GPCRs and could potentially be used to design novel and subtype selective drugs.

Are there differences in the kinetic parameters of the vertical jump performed by beach volleyball players on different types of sand?

Beach volleyball (BV) is an intermittent sport characterised by short-duration and highly demanding activities with low intensity periods. Establishing if players' jump ability is influenced by sand granulometry is a useful information for sport scientists, coaches and players. This study aimed to assess the possible differences in the kinetics parameters of the vertical jump on different types of sand performed by BV players. Twelve elite female players performed six countermovement jumps (CMJs) in three different surface conditions (fine sand, reference, coarse sand) in a random counterbalanced order (216 jumps). A generalised mixed model approach detected differences for CMJ model in total duration (p: 0.016), eccentric phase duration (p: 0.007), concentric phase duration (p: 0.011), time to peak power (p: < 0.001), time to peak force (p: 0.014), maximum rate force development concentric phase (p: 0.004), maximum velocity (p: 0.028) and peak power eccentric (p: 0.018). Coarse sand decreases the time spent jumping compared to fine sand, without a penalty to jump height. Coaches and athletes should take this information into account to enhance their understanding of practice strategies and game conditions. One might anticipate a faster pace in games played on coarse sand and a slower pace on fine sand.

Large cell carcinoma of the lung: LDCT features and survival in screen-detected cases.

PURPOSE: To investigate the early radiological features and survival of Large Cell Carcinoma (LCC) cases diagnosed in low-dose computed tomography (LDCT) screening trials. METHODS: Two radiologists jointly reviewed the radiological features of screen-detected LCCs observed in NLST, ITALUNG, and LUSI trials between 2002 and 2016, comprising a total of 29,744 subjects who underwent 3-5 annual screening LDCT examinations. Survival or causes of death were established according to the mortality registries extending more than 12 years since randomization. RESULTS: LCC was diagnosed in 30 (4 %) of 750 subjects with screen-detected lung cancer (LC), including 15 prevalent and 15 incident cases. Three additional LCCs occurred as interval cancers during the screening period. LDCT images were available for 29 cases of screen-detected LCCs, and 28 showed a single, peripheral, and well-defined solid nodule or mass with regularly smooth (39 %), lobulated (43 %), or spiculated (18 %) margins. One case presented as hilar mass. In 9 incident LCCs, smaller solid nodules were identified in prior LDCT examinations, allowing us to calculate a mean Volume Doubling Time (VDT) of 98.7 ± 47.8 days. The overall five-year survival rate was 50 %, with a significant (p = 0.0001) difference between stages I-II (75 % alive) and stages III-IV (10 % alive). CONCLUSIONS: LCC is a fast-growing neoplasm that can escape detection by annual LDCT screening. LCC typically presents as a single solid peripheral nodule or mass, often with lobulated margins, and exhibits a short VDT. The 5-year survival reflects the stage at diagnosis.

Linkers in Bitopic Agonists Shape Bias Profile among Transducers for the Dopamine D2 and D3 Receptors.

Bitopic ligands bind both orthosteric and allosteric or secondary binding sites within the same receptor, often resulting in an improvement of receptor selectivity, potency, and efficacy. In particular, for both agonists and antagonists of the dopamine D2 and D3 receptors (D2R and D3R), the primary therapeutic targets for several neurological and neuropsychiatric disorders, bitopic ligand design has proved advantageous in achieving better pharmacological profiles in vitro. Although the two pharmacophores within a bitopic ligand are typically considered the main drivers of conformational change for a receptor, the role of the linker that connects the two has not yet been systematically studied for its relevance in receptor activity profiles. Here, we present a comprehensive analysis of sumanirole and PF592,379-based indole-containing bitopic compounds in agonist activity at D2R and D3R, with a focus on linker chemical space and stereochemistry through testing six distinct chirally resolved linkers and a simple aliphatic linker. The structure activity relationships (SARs) of these linkers are examined extensively, beyond the conventional level, by characterizing the activation of all putative transducers over a 44 min time course. Our multiparametric analysis reveals previously unappreciated specific linker-dependent effects on primary pharmacophores, receptors, transducer activation kinetics, and bias, highlighting the utility of this comprehensive approach and the significance of the linker type in shaping transducer bias profiles.

Early Candida colonisation impact on patients and healthcare professionals in an intensive care unit.

OBJECTIVES: Candida spp. is an opportunistic pathogen that causes superficial and invasive infections with nosocomial outbreaks without strict hygiene protocols. Herein, we assessed oral colonisation by Candida spp. in 209 Intensive Care Unit (ICU) patients between July 2021 and April 2022, conducting clinical, epidemiological, and microbiological characterisation of those developing oral or invasive candidiasis. METHODS: Initial oral swabs were collected within 24 h of admission in the ICU, followed by collections on Days 2, 4, 6 and 8. Swabs from denture-wearing patients, abiotic surfaces, healthcare professionals' hands, and retroauricular regions were also obtained. Recovered yeasts and filamentous fungi were identified using MALDI-TOF MS and morphological characteristics, respectively. Genetic similarity of Candida spp. isolates was evaluated using Amplified fragment length polymorphism (AFLP), and the antifungal susceptibility profile was determined by broth microdilution. RESULTS: In the study, 64.11% of patients were orally colonised by Candida spp. Of these, 80.59% were colonised within the first 24 h. Oral colonisation also occurred on subsequent days: 50%/Day 2, 26.92%/Day 4, and 11.53%/Days 6 and 8. Of the patients, 8.61% had oral candidiasis, mainly pseudomembranous. Among orally colonised patients, 2.23% developed invasive candidiasis. Besides, 89.47% of healthcare professionals evaluated were colonised. MALDI-TOF MS identified different yeast species, and C. albicans (45.34%), C. tropicalis (15.7%), and C. parapsilosis sensu stricto (9.88%) were the most prevalent. AFLP analysis indicated a high genetic correlation (≥97%) between C. parapsilosis sensu stricto isolates from patients and professionals. Three resistant C. albicans isolates were also found. CONCLUSION: This study reported a diversity of yeast and filamentous fungi species in ICU patients and highlighted early Candida spp. colonisation risks for invasive candidiasis, as well as the potential horizontal transmission in the nosocomial setting, emphasising the need for effective infection control measures.

Involvement of dopamine D3 receptor in impulsive choice decision-making in male rats.

Impulsive decision-making has been linked to impulse control disorders and substance use disorders. However, the neural mechanisms underlying impulsive choice are not fully understood. While previous PET imaging and autoradiography studies have shown involvement of dopamine and D2/3 receptors in impulsive behavior, the roles of distinct D1, D2, and D3 receptors in impulsive decision-making remain unclear. In this study, we used a food reward delay-discounting task (DDT) to identify low- and high-impulsive rats, in which low-impulsive rats exhibited preference for large delayed reward over small immediate rewards, while high-impulsive rats showed the opposite preference. We then examined D1, D2, and D3 receptor gene expression using RNAscope in situ hybridization assays. We found that high-impulsive male rats exhibited lower levels of D2 and D3, and particularly D3, receptor expression in the nucleus accumbens (NAc), with no significant changes in the insular, prelimbic, and infralimbic cortices. Based on these findings, we further explored the role of the D3 receptor in impulsive decision-making. Systemic administration of a selective D3 receptor agonist (FOB02-04) significantly reduced impulsive choices in high-impulsive rats but had no effects in low-impulsive rats. Conversely, a selective D3 receptor antagonist (VK4-116) produced increased both impulsive and omission choices in both groups of rats. These findings suggest that impulsive decision-making is associated with a reduction in D3 receptor expression in the NAc. Selective D3 receptor agonists, but not antagonists, may hold therapeutic potentials for mitigating impulsivity in high-impulsive subjects.

Using EEG total energy as a noninvasively tracking of intracranial (and cerebral perfussion) pressure in an animal model: A pilot study.

PURPOSE: This study aims to describe the total EEG energy during episodes of intracranial hypertension (IH) and evaluate its potential as a classification feature for IH. NEW METHODS: We computed the sample correlation coefficient between intracranial pressure (ICP) and the total EEG energy. Additionally, a generalized additive model was employed to assess the relationship between arterial blood pressure (ABP), total EEG energy, and the odds of IH. RESULTS: The median sample cross-correlation between total EEG energy and ICP was 0.7, and for cerebral perfusion pressure (CPP) was 0.55. Moreover, the proposed model exhibited an accuracy of 0.70, sensitivity of 0.53, specificity of 0.79, precision of 0.54, F1-score of 0.54, and an AUC of 0.7. COMPARISON WITH EXISTING METHODS: The only existing comparable methods, up to our knowledge, use 13 variables as predictor of IH, our model uses only 3, our model, as it is an extension of the generalized model is interpretable and it achieves the same performance. CONCLUSION: These findings hold promise for the advancement of multimodal monitoring systems in neurocritical care and the development of a non-invasive ICP monitoring tool, particularly in resource-constrained environments.

Correction: Factors associated with SARS-COV-2 positive test in Lifelines.

[This corrects the article DOI: 10.1371/journal.pone.0294556.].

Cardiac troponin I as predictor for cardiac and other mortality in the German randomized lung cancer screening trial (LUSI).

Cardiac Troponin I (cTnI) could be used to identify individuals at elevated risk of cardiac death in lung cancer (LC) screening settings. In a population-based, randomized LC screening trial in Germany ("LUSI" study) serum cTnI was measured by high-sensitivity assay in blood samples collected at baseline, and categorized into unquantifiable/low (< 6 ng/L), intermediate (≥ 6-15 ng/L), and elevated (≥ 16 ng/L). Cox proportional-hazard models were used to estimate risk of all-cause and cardiac mortality with cTnI levels. After exclusion criteria, 3653 participants were included for our analyses, of which 82.4% had low, 12.8% intermediate and 4.8% elevated cTnI, respectively. Over a median follow up of 11.87 years a total of 439 deaths occurred, including 67 caused by cardiac events. Within the first 5 years after cTnI measurement, intermediate or elevated cTnI levels showed approximately 1.7 (HR = 1.69 [95% CI 0.57-5.02) and 4.7-fold (HR = 4.66 [1.73-12.50]) increases in risk of cardiac death relative to individuals with unquantifiable/low cTnI, independently of age, sex, smoking and other risk factors. Within this time interval, a risk model based on age, sex, BMI, smoking history and cTnI showed a combined area under the ROC curve (AUC) of 73.6 (58.1-87.3), as compared to 70.4 (53.3-83.5) for a model without cTnI. Over the time interval of > 5-10 years after blood donation, the relative risk associations with cTnI and were weaker. cTnI showed no association with mortality from any other (non-cardiac) cause. Our findings show that cTnI may be of use for identifying individuals at elevated risk specifically of short-term cardiac mortality in the context of LC screening.

Telangiectatic osteosarcoma in four dogs: Cytologic, histopathologic, cytochemical, and immunohistochemical findings.

Telangiectatic osteosarcoma is a rare variant of osteosarcoma histologically and clinically similar to hemangiosarcoma (HSA). This case series describes the imaging and cytologic features of four histologically confirmed telangiectatic osteosarcomas, including the use of cytochemical stains. Alkaline phosphatase (ALP) was applied to Wright-Giemsa-stained cytology slides, and Factor VIII immunohistochemistry was evaluated. Cytologic characteristics included atypical mesenchymal cells with evidence of acute and chronic hemorrhage. Telangiectatic osteosarcoma cases had positive ALP cytochemical staining, while control HSA cases were negative. Factor VIII immunohistochemistry was negative in telangiectatic osteosarcoma and positive in HSA. Cytologic diagnosis of telangiectatic osteosarcoma with positive ALP cytochemical staining can help differentiate this neoplasm from HSA.

Association of leukergy (in vitro leukocyte aggregation) with systemic inflammation in dogs and cats (2017-2022).

BACKGROUND: Leukergy is the phenomenon of aggregation of leukocytes on a peripheral blood film, and in humans, it is used as an indicator of systemic inflammation and infection. OBJECTIVES: To assess the association of leukergy on blood film examination with biochemical and clinical evidence of systemic inflammation, infection, neoplasia, or specific organ system disease. METHODS: A case-control study using retrospective analysis (2017-2022) identified all canine and feline patients that had been presented to an academic referral center with a finding of leukergy on peripheral blood film and an equal number of species-matched controls. RESULTS: A total of 127 cases (canine n = 44, feline n = 83) were identified, as well as 127 controls. Feline samples were 7.6× more likely to exhibit leukergy (0.019%) than canine (0.0025%). A positive association was noted between leukergy and higher globulin concentrations in dogs (marginal difference 0.5 mg/dL, P = .016) and cats (marginal difference 0.67 mg/dL, P = <.001). Cats with leukergy had higher WBC counts and were less likely to be diagnosed with cardiac or urinary tract disease than controls. Dogs with leukergy had lower WBC counts and were more likely to be febrile but were less likely to have urinary tract disease than controls. No association was found with neutrophil toxic change or band forms, systemic antimicrobial therapy, or signalment. CONCLUSIONS: We conclude that there is a positive association between increased globulin concentrations and leukergy and inconsistent associations between leukergy and other markers of inflammation or infection. Leukergy is rare overall but markedly more common in cats than dogs.

Abdominal ultrasonographic findings of cats with feline infectious peritonitis: an update.

OBJECTIVES: The aim of this study was to describe the abdominal ultrasonographic findings in cats with confirmed or presumed feline infectious peritonitis (FIP). METHODS: This was a retrospective study performed in an academic veterinary hospital. The diagnosis of FIP was reached on review of history, signalment, clinical presentation, complete blood count, biochemistry panel, peritoneal fluid analysis, cytology and/or histopathology results from abnormal organs, and/or molecular testing (immunohistochemical or FIP coronavirus [FCoV] RT-PCR). Cats with confirmed FIP by molecular testing or with a highly suspicious diagnosis of FIP were included. Abdominal ultrasound examination findings were reviewed. RESULTS: In total, 25 cats were included. Common clinical signs/pathology findings included hyperglobulinemia (96%), anorexia/hyporexia (80%) and lethargy (56%). Abdominal ultrasound findings included effusion in 88% and lymphadenopathy in 80%. Hepatic changes were noted in 80%, the most common being hepatomegaly (58%) and a hypoechoic liver (48%). Intestinal changes were noted in 68% of cats, characterized by asymmetric wall thickening and/or loss of wall layering, with 52% being ileocecocolic junction and/or colonic in location. Splenic changes were present in 36% of cats, including splenomegaly, mottled parenchyma and hypoechoic nodules. Renal changes were present in 32%, encompassing a hypoechoic subcapsular rim and/or cortical nodules. Mesenteric and peritoneal abnormalities were seen in 28% and 16% of cats, respectively. Most cats (92%) had two or more locations of abdominal abnormalities on ultrasound. CONCLUSIONS AND RELEVANCE: The present study documents a wider range and distribution of ultrasonographic lesions in cats with FIP than previously reported. The presence of effusion and lymph node, hepatic and/or gastrointestinal tract changes were the most common findings, and most of the cats had a combination of two or more abdominal abnormalities.

Spindle-cell thymoma colliding with a bronchogenic cyst in a Yorkshire terrier.

An 8-year-old male Yorkshire terrier was presented to the Tufts Veterinary Hospital for evaluation of increased respiratory effort. A mediastinal mass composed of a spindle-cell thymoma within a bronchogenic cyst was diagnosed with computed tomography thoracic imaging, ultrasound-guided fine-needle aspirate biopsy, and histopathologic evaluation after surgical removal. Histologic evaluation showed a multilocular cyst structure as well as a mass characterized by spindle to polygonal thymic epithelial cells. The cyst was characterized by a lining of ciliated pseudostratified respiratory epithelium. To the authors' knowledge, this is the first report of a spindle-cell thymoma being associated with a mediastinal bronchogenic cyst in a dog.

Novel EEG Metric Correlates with Intracranial Pressure in an Animal Model.

BACKGROUND: Intracranial pressure (ICP) can be continuously and reliably measured using invasive monitoring through an external ventricular catheter or an intraparenchymal probe. We explore electroencephalography (EEG) to identify a reliable real-time noninvasive ICP correlate. METHODS: Using a previously described porcine model of intracranial hypertension, we examined the cross correlation between ICP time series and the slope of the EEG power spectral density as described by ϕ. We calculated ϕ as tan-1 (slope of power spectral density) and normalized it by π, where slope is that of the power-law fit (log frequency vs. log power) to the power spectral density of the EEG signal. Additionally, we explored the relationship between the ϕ time series and cerebral perfusion pressure. A total of 11 intracranial hypertension episodes across three different animals were studied. RESULTS: The mean correlation between ϕ angle and ICP was - 0.85 (0.15); the mean correlation with cerebral perfusion pressure was 0.92 (0.02). Significant correlation occurred at zero lag. In the absence of intracranial hypertension, the absolute value of the ϕ angle was greater than 0.9 (mean 0.936 radians). However, during extreme intracranial hypertension causing cerebral circulatory arrest, the ϕ angle is on average below 0.9 radians (mean 0.855 radians). CONCLUSIONS: EEG ϕ angle is a promising real-time noninvasive measure of ICP/cerebral perfusion using surface electroencephalography.

Factors associated with SARS-COV-2 positive test in Lifelines.

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) can affect anyone, however, it is often mixed with other respiratory diseases. This study aimed to identify the factors associated with SARS-COV-2 positive test. METHODS: Participants from the Northern Netherlands representative of the general population were included if filled in the questionnaire about well-being between June 2020-April 2021 and were tested for SARS-COV-2. The outcome was a self-reported test as measured by polymerase chain reaction. The data were collected on age, sex, household, smoking, alcohol use, physical activity, quality of life, fatigue, symptoms and medications use. Participants were matched on sex, age and the timing of their SARS-COV-2 tests maintaining a 1:4 ratio and classified into those with a positive and negative SARS-COV-2 using logistic regression. The performance of the model was compared with other machine-learning algorithms by the area under the receiving operating curve. RESULTS: 2564 (20%) of 12786 participants had a positive SARS-COV-2 test. The factors associated with a higher risk of SARS-COV-2 positive test in multivariate logistic regression were: contact with someone tested positive for SARS-COV-2, ≥1 household members, typical SARS-COV-2 symptoms, male gender and fatigue. The factors associated with a lower risk of SARS-COV-2 positive test were higher quality of life, inhaler use, runny nose, lower back pain, diarrhea, pain when breathing, sore throat, pain in neck, shoulder or arm, numbness or tingling, and stomach pain. The performance of the logistic models was comparable with that of random forest, support vector machine and gradient boosting machine. CONCLUSIONS: Having a contact with someone tested positive for SARS-COV-2 and living in a household with someone else are the most important factors related to a positive SARS-COV-2 test. The loss of smell or taste is the most prominent symptom associated with a positive test. Symptoms like runny nose, pain when breathing, sore throat are more likely to be indicative of other conditions.

Climate-Change Impacts on Cephalopods: A Meta-Analysis.

Aside from being one of the most fascinating groups of marine organisms, cephalopods play a major role in marine food webs, both as predators and as prey, while representing key living economic assets, namely for artisanal and subsistence fisheries worldwide. Recent research suggests that cephalopods are benefitting from ongoing environmental changes and the overfishing of certain fish stocks (i.e., of their predators and/or competitors), putting forward the hypothesis that this group may be one of the few "winners" of climate change. While many meta-analyses have demonstrated negative and overwhelming consequences of ocean warming (OW), acidification (OA), and their combination for a variety of marine taxa, such a comprehensive analysis is lacking for cephalopod molluscs. In this context, the existing literature was surveyed for peer-reviewed articles featuring the sustained (≥24 h) and controlled exposure of cephalopod species (Cephalopoda class) to these factors, applying a comparative framework of mixed-model meta-analyses (784 control-treatment comparisons, from 47 suitable articles). Impacts on a wide set of biological categories at the individual level (e.g., survival, metabolism, behavior, cell stress, growth) were evaluated and contrasted across different ecological attributes (i.e., taxonomic lineages, climates, and ontogenetic stages). Contrary to what is commonly assumed, OW arises as a clear threat to cephalopods, while OA exhibited more restricted impacts. In fact, OW impacts were ubiquitous across different stages of ontogeny, taxonomical lineages (i.e., octopuses, squids, and cuttlefish). These results challenge the assumption that cephalopods benefit from novel ocean conditions, revealing an overarching negative impact of OW in this group. Importantly, we also identify lingering literature gaps, showing that most studies to date focus on OW and early life stages of mainly temperate species. Our results raise the need to consolidate experimental efforts in a wider variety of taxa, climate regions, life stages, and other key environmental stressors, such as deoxygenation and hypoxia, to better understand how cephalopods will cope with future climate change.

Vulval apocrine adenocarcinoma with tumour-associated eosinophilia in a cat.

A 10-year-old, spayed female, Domestic Shorthaired cat was referred for surgical removal of a mass on the left vulval fold. An impression smear revealed mixed cell inflammation, with eosinophils predominating focally, and a concurrent bacterial infection, suggesting a primarily inflammatory lesion. However, cytology of a fine-needle aspirate of the mass revealed a neoplastic epithelial cell population, confirmed on histopathology as an apocrine vulval adenocarcinoma with lymphatic invasion and marked tumour-associated tissue eosinophilia. One month after surgical excision of the mass, the cat developed inguinal metastatic lymphadenopathy and chemotherapy was initiated. The patient ultimately developed marked peripheral lymphadenomegaly and was euthanized due to concerns for overall quality of life and comfort. This case highlights that neoplasia should be a consistent differential diagnosis for eosinophilic infiltrates/inflammation. The distinct appearance of the two cytological samples in this case stresses the need for sampling of different sites of a lesion and the importance of not relying on superficial impression smears for clinical management and prognosis.