Miracle-dz/UniFAR-FTUs huggingface dataset:
Live Tissue Imaging Reveals Distinct Transcellular Pathways for Organic Cations and Anions at the Blood-Cerebrospinal Fluid Barrier

Formed by the choroid plexus epithelial (CPE) cells, the blood-cerebrospinal fluid barrier (BCSFB) plays an active role in removing drugs, toxins, and metabolic wastes from the brain. Several organic cation and anion transporters are expressed in the CPE cells, but how they functionally mediate transepithelial transport of organic cations and anions remain unclear. In this study, we visualized the transcellular transport of fluorescent organic cation and organic anion probes using live tissue imaging in freshly isolated mouse choroid plexuses (CPs). The cationic probe, 4-[4-(dimethylamino)phenyl]-1-methylpyridinium iodide (IDT307) was transported into CPE cells at the apical membrane and highly accumulated in mitochondria. Consistent with the lack of expression of organic cation efflux transporters, there was little efflux of IDT307 into the blood capillary space. Furthermore, IDT307 uptake and intracellular accumulation was attenuated by approximately 70% in CP tissues from mice with targeted deletion of the plasma membrane monoamine transporter (Pmat). In contrast, the anionic probe fluorescein-methotrexate (FL-MTX) was rapidly transported across the CPE cells into the capillary space with little intracellular accumulation. Rifampicin, an inhibitor of organic anion transporting polypeptides (OATPs), completely blocked FL-MTX uptake into the CPE cells whereas MK-571, a pan-inhibitor of multidrug resistance associated proteins (MRPs), abolished basolateral efflux of FL-MTX. In summary, our results suggest distinct transcellular transport pathways for organic cations and anions at the BCSFB and reveal a pivotal role of PMAT, OATP and MRP transporters in organic cation and anion transport at the blood-cerebrospinal fluid interface. SIGNIFICANCE STATEMENT Live tissue imaging revealed that while organic cations are transported from the cerebrospinal fluid (CSF) into the choroid plexus epithelial cells by plasma membrane monoamine transporter without efflux into the blood, amphipathic anions in the CSF are efficiently transported across the BCSFB through the collaborated function of apical organic anion transporting polypeptides and basolateral multidrug resistance associated proteins. These findings contribute to a mechanistic understanding of the molecular and cellular pathways for choroid plexus clearance of solutes from the brain.
Antibacterial, cytotoxicity and biodegradability studies of polycaprolactone nanofibers holding green synthesized Ag nanoparticles using atropa belladonna extract

Abstract Atropa belladonna is one of the herbs used to treat wounds and prevent inflammation. This study provides a scientific assessment for the wound healing potential of biodegradable nanofibers containing Ag nanoparticles encapsulated with atropa belladonna extract (eAgNPs). Ultraviolet-visible (UV-vis) spectroscopy was used to observe the localized surface plasmon resonance (LSPR) band of AgNPs synthesized from atropa belladonna extract prepared under different conditions. Polycaprolactone (PCL) nanofibers with eAgNPs were fabricated using the electrospinning technique. The distribution of AgNPs and eAgNPs and the size of nanofibers were characterized with scanning and transmission electron microscopy (SEM, TEM) before and after degradation at the end of 18 weeks. Fourier transform infrared (FTIR) spectroscopy showed the surface interactivity between AgNPs, atropa belladonna extract and PCL nanofibers and also approved the modification of PCL nanofibers with eAgNPs. X-ray diffraction analysis (XRD) defined the formation of the crystalline AgNPs and appreciated the orientation of the nanofibers. Results of tension tests revealed that modification of PCL nanofibers with pure AgNPs and eAgNPs significantly increased strength and tensile modulus. Due to the hydrophobic nature of PCL, modification with pure AgNPs and eAgNPs slightly reduced its hydrophobicity. Biodegradation tests of PCL nanofibers with eAgNPs exhibited a higher degradation rate than neat PCL nanofibers. In vitro MTT results revealed that eAgNPs doped PCL samples have better cell viability than AgNPs doped and neat PCL nanofibers. Owing to their antibacterial properties, biodegradation rates, low cytotoxicity, mechanical and surface morphologic properties of AgNPs modified PCL nanofibers containing atropa belladonna are considered to have a great potential for skin regeneration.
Metabolomics paves the way for improved drug target identification

Correctly identifying candidate drugs for protein targets is crucial for drug discovery. Despite the importance of this problem for the pharmaceutical industry, chemical screening remains a challenging task, and drug–target misidentification may contribute to failures in drug development. In their recent study, Sauer and colleagues (Holbrook‐Smith et al, 2022) demonstrate proof‐of‐concept for a new way to identify drug–target interactions using high‐throughput metabolomics, potentially paving the way towards a universal method for predicting drug–target relationships.
Assessing the Accuracy of Bioluminescence Image-Guided Stereotactic Body Radiation Therapy of Orthotopic Pancreatic Tumors Using a Small Animal Irradiator

Stereotactic body radiation therapy (SBRT) has shown promising results in the treatment of pancreatic cancer and other solid tumors. However, wide adoption of SBRT remains limited largely due to uncertainty about the treatment's optimal fractionation schedules to elicit maximal tumor response while limiting the dose to adjacent structures. A small animal irradiator in combination with a clinically relevant oncological animal model could address these questions. Accurate delivery of X rays to animal tumors may be hampered by suboptimal image-guided targeting of the X-ray beam in vivo. Integration of bioluminescence imaging (BLI) into small animal irradiators in addition to standard cone-beam computed tomography (CBCT) imaging improves target identification and high-precision therapy delivery to deep tumors with poor soft tissue contrast, such as pancreatic tumors. Using bioluminescent BxPC3 pancreatic adenocarcinoma human cells grown orthotopically in mice, we examined the performance of a small animal irradiator equipped with both CBCT and BLI in delivering targeted, hypo-fractionated, multi-beam SBRT. Its targeting accuracy was compared with magnetic resonance imaging (MRI)-guided targeting based on co-registration between CBCT and corresponding sequential magnetic resonance scans, which offer greater soft tissue contrast compared with CT alone. Evaluation of our platform's BLI-guided targeting accuracy was performed by quantifying in vivo changes in bioluminescence signal after treatment as well as staining of ex vivo tissues with γH2AX, Ki67, TUNEL, CD31 and CD11b to assess SBRT treatment effects. Using our platform, we found that BLI-guided SBRT enabled more accurate delivery of X rays to the tumor resulting in greater cancer cell DNA damage and proliferation inhibition compared with MRI-guided SBRT. Furthermore, BLI-guided SBRT allowed higher animal throughput and was more cost effective to use in the preclinical setting than MRI-guided SBRT. Taken together, our preclinical platform could be employed in translational research of SBRT of pancreatic cancer.
Preoperative buccal bone volume predicts long‐term graft retention following augmentation in the esthetic zone: A retrospective case series

Abstract Objectives Buccal bone augmentation in the esthetic zone is routinely used to achieve optimal clinical outcomes. Nonetheless, long‐term data are sparse, and it is unknown how baseline buccal bone volume affects the retention of the augmented volume over time. Material and methods This is a long‐term follow‐up retrospective case series. After a preoperative computed tomography scan, implants were placed in the anterior maxilla following guided bone regeneration, autogenous block grafting, or both. At the follow‐up, patients received a computed tomography scan and a clinical examination. Buccal bone volume was the primary outcome. Buccal bone thickness, peri‐implant, and esthetic parameters were secondary outcomes. Results After a median follow‐up of 6.7 years (interquartile range: 4.9–9.4), 28 implants in 19 patients (median age at augmentation: 43.3 years, interquartile range: 34.4–56.7, 53% female) were followed up. Preoperative buccal bone volume at baseline (V0) showed a moderate correlation to final buccal bone volume (Vt, rs = .43) but a strong correlation to the absolute volumetric change (ΔV = Vt–V0, rs = −.80). A linear mixed model for Vt had a large intercept of 91.39 (p < .001) and a rather small slope of . 11 for V0 (p = .11). Observed differences between treatments were not statistically significant in the mixed model. V0 above 105 mm3 predicted a negative volume change (ΔV < 0) with a specificity of 100% and a sensitivity of 96%. Conclusions The results suggest higher gains in sites with lower V0 and point to a cutoff V0 above which the augmented volume is not retained long‐term.
CMV-associated T cell and NK cell terminal differentiation does not affect immunogenicity of ChAdOx1 vaccination

Cytomegalovirus (CMV) is a globally ubiquitous pathogen with a seroprevalence of approximately 50% in the United Kingdom. CMV infection induces expansion of immunosenescent T cell and NK cell populations, with these cells demonstrating lower responsiveness to activation and reduced functionality upon infection and vaccination. In this study, we found that CMV+ participants had normal T cell responses after a single-dose or homologous vaccination with the viral vector chimpanzee adenovirus developed by the University of Oxford (ChAdOx1). CMV seropositivity was associated with reduced induction of IFN-γ–secreting T cells in a ChAd-Modified Vaccinia Ankara (ChAd-MVA) viral vector vaccination trial. Analysis of participants receiving a single dose of ChAdOx1 demonstrated that T cells from CMV+ donors had a more terminally differentiated profile of CD57+PD1+CD4+ T cells and CD8+ T cells expressing less IL-2Rα (CD25) and fewer polyfunctional CD4+ T cells 14 days after vaccination. NK cells from CMV-seropositive individuals also had a reduced activation profile. Overall, our data suggest that although CMV infection enhances immunosenescence of T and NK populations, it does not affect antigen-specific T cell IFN-γ secretion or antibody IgG production after vaccination with the current ChAdOx1 nCoV-19 vaccination regimen, which has important implications given the widespread use of this vaccine, particularly in low- and middle-income countries with high CMV seroprevalence.
Bioefficacy evaluation of ferrocenyl chalcones against Meloidogyne incognita and Sclerotium rolfsii infestation in tomato

Abstract The present study reports, bioefficacy evaluation of effective compounds against Meloidogyne incognita and Sclerotium rolfsii in pot cultured tomato. The identified five most effective compounds, i.e. (2E)-1-(4-Methylphenyl)-3-ferrocenyl-prop-2-en-1-one (6g), (2E)-1-(4-Methoxyphenyl)-3-ferrocenyl-prop-2-en-1-one (6h), (2E)-1-(3-Bromophenyl)-3-ferrocenyl-prop-2-en-1-one (6j), (2E)-1-(2,4-Dichlorophenyl)-3-ferrocenyl-prop-2-en-1-one (6k) and (2E)-1-(3,5-Dichloro-2-hydroxyphenyl)-3-ferrocenyl-prop-2-en-1-one (6p) along with Carbofuran 3G as positive control were tested at 20, 40 and 80 ppm by soil drenching and root dipping methods. The study revealed that all plant growth parameters were positively influenced by these compounds. The presence of an electron releasing group positively influenced the efficacy, and the activity was highest in compounds 6g and 6h at 80 ppm. Based on in vitro results against S. rolfsii, (2E)-1-Ferrocenyl-3-(4-bromophenyl)-prop-2-en-1-one (3b), (2E)-1-Ferrocenyl-3-(2,6-dichlorophenyl)-prop-2-en-1-one (3o) and (2E)-1-(5-Chloro-2-hydroxyphenyl)-3-ferrocenyl-prop-2-en-1-one (6o) along with Tebuconazole 25.9% EC and Hexaconazole 5% SC as positive control were evaluated. The shoot length was found to be highest (24.50 cm) in plants treated with 3b followed by 3o and 6o at 1000 ppm. The percent disease incidence was significantly decreased as compared to control. The percent disease incidence was found to be minimum in plants treated with 3b at 1000 ppm. However, root dipping was not as effective as soil drenching. Therefore, ferrocenyl chalcone derivatives proved to be of great fungicidal and nematicidal potential opening new opportunities for expanding their effectiveness as new pest control agents.
Bias Crime and Victimization Among Latinx Adults: Formal and Informal Help Seeking

Latinx adults have become increasingly vulnerable to bias motivated victimization. The impact of such incidents on Latinx communities is severely understudied, particularly concerning whether or not victims will seek help as a result of such events. Evidence within other victimization contexts demonstrate Latinx populations may be less likely to seek formal help from police, medical providers, and other formal authorities, relying instead on informal support networks such as family and friends. The current study sought to understand formal and informal help-seeking behavior among Latinx adults who experienced bias motivated victimization. The Understanding and Measuring Bias Victimization against Latinos study obtained rates of bias victimization and subsequent help-seeking behavior among Latinx adults who reported experiencing bias victimization (n = 315, 34.6% of full sample of 910). Those who experience bias victimization seek formal help at much lower rates than informal forms of support. Logistic regression analyses controlling the type of victimization demonstrated that participants who experienced a victimization constituting a hate crime were more likely to seek formal help compared to experiencing non-criminal bias events. Implications include addressing barriers to Latinx bias victims seeking forms of help, in addition to understanding the potential polyvictimization histories that predict why Latinx adults may decide to seek help.
Histone demethylase IBM1-mediated meiocyte gene expression ensures meiotic chromosome synapsis and recombination

Histone methylation and demethylation play important roles in plant growth and development, but the involvement of histone demethylation during meiosis is poorly understood. Here we show that disruption of Arabidopsis thaliana INCREASE IN BONSAI METHYLATION 1 (IBM1) causes incomplete synapsis, chromosome entanglement and reduction of recombination during meiosis, leading to sterility. Interestingly, these ibm1 meiotic defects are rescued by mutations in either SUVH4/KYP or CMT3. Using transcriptomic analyses we show that mutation of IBM1 down-regulates thousands of genes expressed in meiocytes, and that expression of about 38% of these genes are restored to wild type levels in ibm1 cmt3 double mutants. Changes in the expression of 437 of these, including the ARABIDOPSIS MEI2-LIKE AML3-5 genes, are correlated with a significant reduction of gene body CHG methylation. Consistently, the aml3 aml4 aml5 triple have defects in synapsis and chromosome entanglement similar to ibm1. Genetic analysis shows that aml3 aml4 aml5 ibm1 quadruple mutants resembles the ibm1 single mutant. Strikingly, over expression of AML5 in ibm1 can partially rescue the ibm1 meiotic defects. Taken together, our results demonstrate that histone demethylase IBM1 is required for meiosis likely via coordinated regulation of meiocyte gene expression during meiosis.
Validation of a single liquid chromatography‐tandem mass spectrometry approach for oxytetracycline determination in bull plasma, seminal plasma and urine

Abstract Oxytetracycline is a broad‐spectrum antibiotic, which inhibits protein synthesis and is generally used for the treatment of pneumonia, shipping fever, leptospirosis and wound infections in cattle and swine. The present work proposes a novel liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for oxytetracycline quantification in bull plasma, seminal plasma and urine, requiring limited sample treatment before analysis. Extraction with trichloroacetic acid followed by dilution of the supernatant in mobile phase proved to be effective in all three matrices, allowing to rapidly process large batches of samples. Sharp and symmetrical peak shape was obtained using a BEH C18 reversed‐phase column in a chromatographic run of just 3.5 min. The mass spectrometer operated in positive electrospray ionization mode and monitored specific transitions for oxytetracycline (461.1 → 425.8) and the internal standard demeclocycline (465.0 → 447.6). The method was validated over concentration ranges suitable for field concentrations of oxytetracycline found in each matrix, showing good linearity during each day of testing (R 2 always >0.99), as also confirmed by analysis of variance (ANOVA) and lack‐of‐fit tests. Excellent accuracy and precision were demonstrated by calculated bias always within ±15% and CV% below 10% at all quality control (QC) levels in the three matrices. Matrix effect and recovery were investigated for both analytes, which showed consistent and comparable behaviour in each matrix. To our knowledge, this is the first validated approach for mass spectrometric determination of oxytetracycline in seminal plasma and urine. The method was successfully applied to samples collected during a pharmacokinetic study in bulls, allowing to assess the oxytetracycline concentration–time profile in plasma, seminal plasma and urine.
Sodium houttuyfonate enhances the mono-therapy of fluconazole on oropharyngeal candidiasis (OPC) through HIF-1α/IL-17 axis by inhibiting cAMP mediated filamentation in Candida albicans-Candida glabrata dual biofilms

ABSTRACT Candida albicans and Candida glabrata are two common opportunistic fungi that can be co-isolated in oropharyngeal candidiasis (OPC). Hypha is a hallmark of the biofilm formation of C. albicans, indispensable for the attachment of C. glabrata, which is seldom in mycelial morphology. Increasing evidence reveals a hypoxic microenvironment in interior fungal biofilms, reminding of a fact that inflammation is usually accompanied by oxygen deprivation. As a result, it is assumed that the disaggregation of hypha-mediated hypoxia of biofilms might be a solution to alleviate OPC. Based on this hypothesis, sodium houttuyfonate (SH), a well-identified traditional herbal compound with antifungal activity, is used in combination with fluconazole (FLU), a well-informed synthesized antimycotics, to investigate their impact on filamentation in C. albicans and C. glabrata dual biofilms and the underlying mechanism of their combined treatment on OPC. The results show that compared with the single therapy, SH plus FLU can inhibit the hyphal growth in the mixed biofilms in vitro, decrease the fungal burden of oral tissues and internal organs, restore mucosal epithelial integrity and function, and reduce hypoxic microenvironment and inflammation in a mice OPC model. The possible mechanism of the combined therapy of SH plus FLU can be attributed to the regulation of HIF-1α/IL-17A axis through direct abrogation of the dual Candida biofilm formation. This study highlights the role of HIF-1α/IL-17A axis and the promising application of SH as a sensitizer of conventional antifungals in the treatment of OPC.
Deep demersal fish communities respond rapidly to warming in a frontal region between Arctic and Atlantic waters

The assessment of climate impact on marine communities dwelling deeper than the well‐studied shelf seas has been hampered by the lack of long‐term data. For a long time, the prevailing expectation has been that thermal stability in deep ocean layers will delay ecosystem responses to warming. Few observational studies have challenged this view and indicated that deep organisms can respond exceptionally fast to physical change at the sea surface. To address the depth‐specific impact of climate change, we investigated spatio‐temporal changes in fish community structure along a bathymetry gradient of 150–1500 m between 1998 and 2016 in East Greenland. Here, the Arctic East Greenland Current and the Atlantic Irminger Current meet and mix, representing a sub‐Arctic transition zone. We found the strongest signals of community reorganizations at depths between 350 and 1000 m and only weak responses in the shallowest and deepest regions. Changes were in synchrony with atmospheric warming, loss in sea ice and variability in physical sea surface conditions both within our study region and North of the Denmark Strait. These results suggest that interannual variability and long‐term climate trends of the larger ecoregion can rapidly affect fish communities down to 1000‐m depth through atmospheric ocean coupling and food web interactions.
Differentially Private Regression with Unbounded Covariates

We provide computationally efficient, differentially private algorithms for the classical regression settings of Least Squares Fitting, Binary Regression and Linear Regression with unbounded covariates. Prior to our work, privacy constraints in such regression settings were studied under strong a priori bounds on covariates. We consider the case of Gaussian marginals and extend recent differentially private techniques on mean and covariance estimation (Kamath et al., 2019; Karwa and Vadhan, 2018) to the sub-gaussian regime. We provide a novel technical analysis yielding differentially private algorithms for the above classical regression settings. Through the case of Binary Regression, we capture the fundamental and widely-studied models of logistic regression and linearly-separable SVMs, learning an unbiased estimate of the true regression vector, up to a scaling factor.
Variational problems on Riemannian manifolds with constrained accelerations

We introduce variational problems on Riemannian manifolds with constrained acceleration and derive necessary conditions for normal extremals in the constrained variational problem. The problem consists on minimizing a higher-order energy functional, among a set of admissible curves defined by a constraint on the covariant acceleration. In addition, we use this framework to address the elastic splines problem with obstacle avoidance in the presence of this type of contraints.