Miracle-dz/UniFAR-FTUs huggingface dataset:
Segmentation of PET Images for Computer-Aided Functional Quantification of Tuberculosis in Small Animal Models

Pulmonary infections often cause spatially diffuse and multi-focal radiotracer uptake in positron emission tomography (PET) images, which makes accurate quantification of the disease extent challenging. Image segmentation plays a vital role in quantifying uptake due to the distributed nature of immuno-pathology and associated metabolic activities in pulmonary infection, specifically tuberculosis (TB). For this task, thresholding-based segmentation methods may be better suited over other methods; however, performance of the thresholding-based methods depend on the selection of thresholding parameters, which are often suboptimal. Several optimal thresholding techniques have been proposed in the literature, but there is currently no consensus on how to determine the optimal threshold for precise identification of spatially diffuse and multi-focal radiotracer uptake. In this study, we propose a method to select optimal thresholding levels by utilizing a novel intensity affinity metric within the affinity propagation clustering framework. We tested the proposed method against 70 longitudinal PET images of rabbits infected with TB. The overall dice similarity coefficient between the segmentation from the proposed method and two expert segmentations was found to be 91.25 ±8.01% with a sensitivity of 88.80 ±12.59% and a specificity of 96.01 ±9.20%. High accuracy and heightened efficiency of our proposed method, as compared to other PET image segmentation methods, were reported with various quantification metrics.
Coordinating Vision and Action in Natural Behaviour: Differences in Spatiotemporal Coupling in Everyday Tasks

Vision and action are tightly coupled in space and time: for many tasks we must look at the right place at the right time to gather the information that we need to complete our behavioural goals. Vision typically leads action by about 0.5 seconds in many natural tasks. However, the factors that influence this temporal coordination are not well understood, and variations have been found previously between two domestic tasks each with similar constraints: tea making and sandwich making. This study offers a systematic exploration of the factors that govern spatiotemporal coordination of vision and action within complex real-world activities. We found that the temporal coordination eye movements and action differed between tea making and sandwich making. Longer eye–hand latencies, more “look ahead” fixations and more looks to irrelevant objects were found when making tea than when making a sandwich. Contrary to previous suggestions, we found that the requirement to move around the environment did not influence the coordination of vision and action. We conclude that the dynamics of visual behaviour during motor acts are sensitive to the task and specific objects and actions required but not to the spatial demands requiring movement around an environment. La vision et l’action sont étroitement liées dans le temps et l’espace : pour bon nombre de tâches, nous devons regarder au bon endroit et au bon moment pour recueillir les informations dont nous avons besoin pour atteindre nos objectifs comportementaux. La vision mène à l’action en plus ou moins 0,5 seconde dans la majorité des tâches que nous effectuons naturellement. Or, les facteurs qui influencent la coordination temporelle ne sont pas bien compris et des variations ont été constatées entre deux tâches domestiques présentant des contraintes similaires : la préparation du thé et la préparation de sandwich. Cette étude propose une exploration systématique des facteurs qui gouvernent la coordination spatio-temporelle de la vision et de l’action lors de la pratique d’activités complexes réelles. Nous avons trouvé que la coordination temporale des mouvements oculaires différait selon que l’on préparait du thé ou des sandwichs. Nous avons noté des latences oeil-main plus longues, un plus haut taux de fixations « vers l’avant » et de regards vers des objets non pertinents lors de la préparation de thé que lors de la préparation de sandwich. Contrairement aux suggestions antérieures, nous avons constaté que le besoin de se déplacer dans un environnement n’influençait pas la coordination de la vision et de l’action. Nous en concluons que la dynamique du comportement visuel durant les actions motrices est sensible à la tâche et aux objets spécifiques et aux actions requises mais pas aux exigences spatiales nécessitant un déplacement dans un environnement.
Increased expression of triggering receptor expressed on myeloid cells 1 and 2 in inflamed human gingiva

BACKGROUND AND OBJECTIVE Periodontitis is an infectious disease in which the host immune and inflammatory responses play essential roles in resistance to bacterial infection, as well as the induction of tissue destruction if the immune response is dysregulated. The triggering receptor expressed on myeloid cells (TREMs) modulates inflammatory and innate immune signaling. TREM-1 is considered as an amplifier of the immune response, while TREM-2 is a negative regulator that has yet to be explored in periodontal disease before. We hypothesized that TREMs participated in the innate immune responses during the pathogenesis of periodontitis. Therefore, the aim of this study was to evaluate TREM-1 and TREM-2 expression in the gingival tissues from patients with chronic periodontitis and healthy subjects as well as their correlation with clinical periodontal parameters. This study is the first to identify TREM-2 in periodontal tissue, as well as the protein expression changes of TREM-1 and TREM-2 in periodontal tissues. MATERIAL AND METHODS Gingival tissue sections were collected from 31 healthy subjects and 53 patients with chronic periodontitis. Immunohistochemistry and quantitative real-time polymerase chain reaction were employed to evaluate the protein and mRNA expression of these receptors in gingival tissues. The recorded clinical parameters were probing depth, clinical attachment loss, plaque index and bleeding on probing. RESULTS In addition to myeloid cells in gingival connective tissues, TREM-1 and TREM-2 were also found expressed in gingival epithelial cells. In particular, TREM-1 was detected in almost all gingival epithelium from both healthy and inflamed biopsies. The expression levels of TREM-1 and TREM-2 were significantly increased in the periodontitis group compared to the healthy group. Increased levels of these receptors are to be positively correlated with site-specific periodontal parameters. CONCLUSION The increased expression of TREM-1 and TREM-2 levels in periodontitis may confer diagnostic and potential therapeutic targets as well as indicating their association with the clinical severity of the disease.
Specificity of Lipoxygenase Pathways Supports Species Delineation in the Marine Diatom Genus Pseudo-nitzschia

Oxylipins are low-molecular weight secondary metabolites derived from the incorporation of oxygen into the carbon chains of polyunsaturated fatty acids (PUFAs). Oxylipins are produced in many prokaryotic and eukaryotic lineages where they are involved in a broad spectrum of actions spanning from stress and defense responses, regulation of growth and development, signaling, and innate immunity. We explored the diversity in oxylipin patterns in the marine planktonic diatom Pseudo-nitzschia. This genus includes several species only distinguishable with the aid of molecular markers. Oxylipin profiles of cultured strains were obtained by reverse phase column on a liquid chromatograph equipped with UV photodiode detector and q-ToF mass spectrometer. Lipoxygenase compounds were mapped on phylogenies of the genus Pseudo-nitzschia inferred from the nuclear encoded hyper-variable region of the LSU rDNA and the plastid encoded rbcL. Results showed that the genus Pseudo-nitzschia exhibits a rich and varied lipoxygenase metabolism of eicosapentaenoic acid (EPA), with a high level of specificity for oxylipin markers that generally corroborated the genotypic delineation, even among genetically closely related cryptic species. These results suggest that oxylipin profiles constitute additional identification tools for Pseudo-nitzschia species providing a functional support to species delineation obtained with molecular markers and morphological traits. The exploration of the diversity, patterns and plasticity of oxylipin production across diatom species and genera will also provide insights on the ecological functions of these secondary metabolites and on the selective pressures driving their diversification.
Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC‐0853, a Selective Reversible Bruton's Tyrosine Kinase Inhibitor

GDC‐0853 is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that is highly selective and noncovalent, leading to reversible binding. In double‐blind, randomized, and placebo‐controlled phase I healthy volunteer studies, GDC‐0853 was well tolerated, with no dose‐limiting adverse events (AEs) or serious AEs. The maximum tolerated dose was not reached during dose escalation (≤600 mg, single ascending dose (SAD) study; ≤250 mg twice daily (b.i.d.) and ≤500 mg once daily, 14‐day multiple ascending dose (MAD) study). Plasma concentrations peaked 1–3 hours after oral administration and declined thereafter, with a steady‐state half‐life ranging from 4.2–9.9 hours. Independent assays demonstrated dose‐dependent BTK target engagement. Based on pharmacokinetic/pharmacodynamic (PK/PD) simulations, a once‐daily dosing regimen (e.g., 100 mg, q.d.) is expected to maintain a high level of BTK inhibition over the dosing interval. Taken together, the safety and PK/PD data support GDC‐0853 evaluation in rheumatoid arthritis, lupus, and other autoimmune or inflammatory indications.
Metabolism and Disposition of a Novel B-Cell Lymphoma-2 Inhibitor Venetoclax in Humans and Characterization of Its Unusual Metabolites

Venetoclax (ABT-199), a B-cell lymphoma-2 (Bcl-2) protein inhibitor, is currently in clinical development for the treatment of hematologic malignancies. We characterized the absorption, metabolism, and excretion of venetoclax in humans. After a single oral dose of [14C]venetoclax to healthy volunteers, the recovery of total radioactive dose was 100%, with feces being the major route of elimination of the administered dose, whereas urinary excretion was minimal (<0.1%). The extent of absorption was estimated to be at least 65%. Venetoclax was primarily cleared by hepatic metabolism (∼66% of the administered dose). ∼33% of the administered dose was recovered as the parent drug and its nitro reduction metabolite M30 [2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-amino-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(4-((4ʹ-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1ʹ-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide] (13%) in feces. Biotransformation of venetoclax in humans primarily involves enzymatic oxidation on the dimethyl cyclohexenyl moiety, followed by sulfation and/or nitro reduction. Nitro reduction metabolites were likely formed by gut bacteria. Unchanged venetoclax was the major drug-related material in circulation, representing 72.8% of total plasma radioactivity. M27 (oxidation at the 6 position of cyclohexenyl ring followed by cyclization at the α-carbon of piperazine ring; 4-[(10aR,11aS)-7-(4-chlorophenyl)-9,9-dimethyl-1,3,4,6,8,10,10a,11a-octahydropyrazino[2,1-b][1,3]benzoxazin-2-yl]-N-[3-nitro-4-(tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide) was identified as a major metabolite, representing 12% of total drug-related material. M27 was primarily formed by cytochrome P450 isoform 3A4 (CYP3A4). Steady-state plasma concentrations of M27 in human and preclinical species used for safety testing suggested that M27 is a disproportionate human metabolite. M27 is not expected to have clinically relevant on- or off-target pharmacologic activities.
Periodontal manifestations of inflammatory bowel disease: emerging epidemiologic and biologic evidence

Inflammatory bowel disease and periodontitis are both described as a disproportionate mucosal inflammatory response to a microbial environment in susceptible patients. Moreover, these two conditions share major environmental and lifestyle-related risk factors. Despite this intriguing pathogenic parallel, large-scale studies and basic research have only recently considered periodontal outcomes as relevant data. There are mounting and consistent arguments, from recent epidemiologic studies and animal models, that these two conditions might be related. This article is a comprehensive and critical up-to-date review of the current evidence and future prospects in understanding the biologic and epidemiologic relationships between periodontal status and inflammatory bowel disease.
Effect of Molasses Feeding on Biochemical and Hormonal Parameters in Sahiwal and Karan Fries Heifers

The present study was designed to investigate the effect of molasses feeding on biochemical and hormonal parameters in Sahiwal and Karan Fries heifers under two feeding regimes, i.e. feeding regime-1, as per the NRC (2001) and feeding regime-2 having 15 % higher energy (supplementation of molasses) than NRC (2001). Twelve healthy heifers (18-24 month) of each Sahiwal and Karan Fries were selected from Livestock Research Centre (LRC) of ICAR-National Dairy Research Institute (ICARNDRI). An initial 15 days were maintained as adaptation period for both feeding regimes. Actual experiment was conducted from 16th day onward for next 15 days. Blood samples were taken on 1st, 7th, 14th, 15th, and 16th day of each feeding regimes and analysed for various biochemical and hormonal parameters. The plasma glucose, Triiodothyronine (T 3 ) and Thyroxin (T 4 ) were signifi cantly (p<0.05) higher during feeding regimes-2 as compared to feeding regimes-1 in both the breeds, while the plasma BUN levels were signifi cantly lower during feeding regimes-2. The plasma NEFA level was found to be higher during feeding regimes-1 as compared to feeding regimes-2 in Sahiwal heifers. It is concluded that molasses supplementation in feed enhances the growth performance and reduces the non esterifi ed fatty acid in both Sahiwal and Karan Fries heifers.
Holocene Dust Transport to the Sub-Antarctic - Implications for the mid-latitude westerlies

Understanding the past behaviour of the Southern Hemisphere mid-latitude westerlies in the past is important due to their role in determining precipitation regimes on Southern Hemisphere land masses, advecting heat and influencing carbon cycling in the Southern Ocean and the transport of mineral and biological matter between continents. The aim of this study was to determine how the Southern Hemisphere mid-latitude westerly winds varied in their strength and intensity over the mid to late Holocene (~5500 cal yr BP to present). Australian dust transport to ombrotrophic (rainfall-fed) peat bogs on Campbell Island (52°34’S, 169°09’E) and Stewart Island (47°00’S, 168°50’E) was assessed. Ombrotrophic bogs grow above the surrounding hydrology and so are isolated from local contributions of sediment (fluvial or colluvial). Subsequently, the majority of mineral matter present in the cores analysed in this study was transported from the Australian mainland into the bogs by the westerly winds. Rates of dust deposition were determined by loss-on ignition analysis and the provenance of dust was determined using a mass balance approach which compared the chemistry of samples in the core to a range of over 250 potential source sediments. Rates of dust deposition and the provenance of dust were used to determine palaeo-aridity patterns on the Australian mainland, which were then used to infer the likely latitudinal position of westerly winds at particular points in time. Patterns of changing grain size were used to determine the changing intensity of the westerly winds. From ~5500-4000 cal yr BP, the results of this study indicate a southward displacement and weak nature of the westerlies. From ~4000-1700 cal yr BP, results indicate a northward displacement and strengthening of the westerlies. The westerlies remained in their northerly location after ~1700 cal yr BP, whilst wind intensity fluctuated. Results suggest that overall, the westerly winds have moved northward and increased in intensity since ~5500 cal yr BP.
Tumor-derived IL-18 induces PD-1 expression on immunosuppressive NK cells in triple-negative breast cancer

Purpose While the inflammatory cytokine interleukin-18 (IL-18) is known to activate natural killer (NK) cells, its precise role in cancer is controversial. In this study, we investigated the role of tumor-derived IL-18 on peripheral blood NK cells in breast cancer patients. Results In breast cancer cell lines, IL-18 was expressed and secreted in the triple-negative breast cancer (TNBC) cell lines MDA-MB-231 and HCC-70 but not in MCF-7 cells. The immature and non-cytotoxic CD56dimCD16dim/− NK cell fraction was increased following co-culture with MDA-MB-231 cells, and this increase was not observed with tumor cells transfected with siRNA for IL-18 or in MCF-7 cells. In addition, tumor-derived IL-18 increased PD-1 expression on CD56dimCD16dim/− NK cells, although no effect on PD-L1 expression in tumor cells was observed. Among EBC patients, serum IL-18 levels were significantly increased in those with a TNBC subtype compared to levels from patients with other subtypes, and the IL-18 levels were strongly associated with poor survival. Similarly, serum IL-18 and CD56dimCD16dim/− NK cells were also increased in patients with metastatic TNBC who had progressive disease following cytotoxic chemotherapy. Experimental Design We performed in vitro experiments in breast cancer cell lines, measured cytokine levels by RT-qPCR, western blot, and ELISA, and analyzed NK cell subsets by flow cytometry. For clinical validation, we collected and analyzed blood sample from patients with early breast cancer (EBC, N = 545) and metastatic breast cancer (MBC, N = 42). Conclusions Our data revealed that tumor-derived IL-18 is associated with bad prognosis in patients with TNBC. Tumor-derived IL-18 increased the immunosuppressive CD56dimCD16dim/− NK cell fraction and induced PD-1 expression on these NK cells.
Transporter Expression in Liver Tissue from Subjects with Alcoholic or Hepatitis C Cirrhosis Quantified by Targeted Quantitative Proteomics

Although data are available on the change of expression/activity of drug-metabolizing enzymes in liver cirrhosis patients, corresponding data on transporter protein expression are not available. Therefore, using quantitative targeted proteomics, we compared our previous data on noncirrhotic control livers (n = 36) with the protein expression of major hepatobiliary transporters, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug and toxin extrusion protein 1 (MATE1), multidrug resistance–associated protein (MRP)2, MRP3, MRP4, sodium taurocholate–cotransporting polypeptide (NTCP), organic anion–transporting polypeptides (OATP)1B1, 1B3, 2B1, organic cation transporter 1 (OCT1), and P-glycoprotein (P-gp) in alcoholic (n = 27) and hepatitis C cirrhosis (n = 30) livers. Compared with control livers, the yield of membrane protein from alcoholic and hepatitis C cirrhosis livers was significantly reduced by 56 and 67%, respectively. The impact of liver cirrhosis on transporter protein expression was transporter-dependent. Generally, reduced protein expression (per gram of liver) was found in alcoholic cirrhosis livers versus control livers, with the exception that the expression of MRP3 was increased, whereas no change was observed for MATE1, MRP2, OATP2B1, and P-gp. In contrast, the impact of hepatitis C cirrhosis on protein expression of transporters (per gram of liver) was diverse, showing an increase (MATE1), decrease (BSEP, MRP2, NTCP, OATP1B3, OCT1, and P-gp), or no change (BCRP, MRP3, OATP1B1, and 2B1). The expression of hepatobiliary transporter protein differed in different diseases (alcoholic versus hepatitis C cirrhosis). Finally, incorporation of protein expression of OATP1B1 in alcoholic cirrhosis into the Simcyp physiologically based pharmacokinetics cirrhosis module improved prediction of the disposition of repaglinide in liver cirrhosis patients. These transporter expression data will be useful in the future to predict transporter-mediated drug disposition in liver cirrhosis patients.
Recurrent depressive symptoms and the incidence of dementia and mild cognitive impairment

Objective: A history of depression has been linked to an increased dementia risk. This risk may be particularly high in recurrent depression due to repeated brain insult. We investigated whether there is a dose-dependent relationship between the number of episodes of elevated depressive symptoms (EDS) and the risk for mild cognitive impairment (MCI) and dementia. Methods: A total of 1,239 older adults from the Baltimore Longitudinal Study of Aging were followed for a median of 24.7 years. Diagnoses of MCI and dementia were made based on prospective data. Participants completed the Center for Epidemiologic Studies Depression Scale at 1- to 2-year intervals and were considered to have an EDS if their score was ≥16. Kaplan-Meier survival curves, log-rank test for trend for survivor functions, and Cox proportional hazards models were conducted to examine the risk of MCI and dementia by number of EDS. Results: We observed a monotonic increase in risk for all-cause dementia and Alzheimer disease as a function of the number of EDS. Each episode was associated with a 14% increase in risk for all-cause dementia. Having 1 EDS conferred an 87%–92% increase in dementia risk, while having 2 or more episodes nearly doubled the risk. Recurrence of EDS did not increase the risk of incident MCI. Conclusions: Our findings support the hypothesis that depression is a risk factor for dementia and suggest that recurrent depression is particularly pernicious. Preventing the recurrence of depression in older adults may prevent or delay the onset of dementia.