Miracle-dz/UniFAR-FTUs huggingface dataset:
Design, synthesis, and evaluation of novel benzoylhydrazone derivatives as Nur77 modulators with potent antitumor activity against hepatocellular carcinoma

Abstract Nur77 modulators have emerged as a promising therapeutic approach for hepatocellular carcinoma. In this study, a structure-based rational drug design approach was used to design and synthesise a series of 4-((8-hydroxy-2-methylquinolin-4-yl)amino)benzoylhydrazone derivatives based on the binding characteristics of our previously reported 10g and the native ligand 3NB at the binding Site C of Nur77. Cell-based cytotoxicity assays revealed that compound TMHA37 demonstrated the highest cytotoxicity against all tested cancer cells. The induced fit docking and binding pose metadynamics simulation suggested that TMHA37 was the most promising Nur77 binder at Site C. Molecular dynamics simulation validated the stable binding of TMHA37 to Nur77’s Site C but not to Sites A or B. Specifically, TMHA37 bound strongly to Nur77-LBD (KD = 445.3 nM) and could activate Nur77’s transcriptional activity. Furthermore, TMHA37 exhibited antitumor effects by blocking the cell cycle at G2/M phase and inducing cell apoptosis in a Nur77-dependent manner.
Molecular Characterization and Sterol Profiles Identify Nonsynonymous Mutations in ERG2 as a Major Mechanism Conferring Reduced Susceptibility to Amphotericin B in Candida kefyr

Some yeast species exhibit intrinsic resistance or rapidly acquire resistance to azole antifungals. Despite >50 years of clinical use, resistance to amphotericin B (AMB) among yeast species has been extremely rarely reported until recently. ABSTRACT The molecular basis of reduced susceptibility to amphotericin B (rs-AMB) among any yeasts is poorly defined. Genetic alterations in genes involved in ergosterol biosynthesis and total cell sterols were investigated among clinical Candida kefyr isolates. C. kefyr isolates (n = 81) obtained from 74 patients in Kuwait and identified by phenotypic and molecular methods were analyzed. An Etest was initially used to identify isolates with rs-AMB. Specific mutations in ERG2 and ERG6 involved in ergosterol biosynthesis were detected by PCR sequencing. Twelve selected isolates were also tested by the SensiTitre Yeast One (SYO), and total cell sterols were evaluated by gas chromatography-mass spectrometry and ERG3 and ERG11 sequencing. Eight isolates from 8 patients showed rs-AMB by Etest, including 2 isolates with additional resistance to fluconazole or to all three antifungals. SYO correctly identified 8 of 8 rs-AMB isolates. A nonsynonymous mutation in ERG2 was detected in 6 of 8 rs-AMB isolates but also in 3 of 73 isolates with a wild-type AMB pattern. One rs-AMB isolate contained a deletion (frameshift) mutation in ERG2. One or more nonsynonymous mutations was detected in ERG6 in 11 of 81 isolates with the rs-AMB or wild-type AMB pattern. Among 12 selected isolates, 2 and 2 isolates contained a nonsynonymous mutation(s) in ERG3 and ERG11, respectively. Ergosterol was undetectable in 7 of 8 rs-AMB isolates, and the total cell sterol profiles were consistent with loss of ERG2 function in 6 rs-AMB isolates and loss of ERG3 activity in another rs-AMB isolate. Our data showed that ERG2 is a major target conferring rs-AMB in clinical C. kefyr isolates. IMPORTANCE Some yeast species exhibit intrinsic resistance or rapidly acquire resistance to azole antifungals. Despite >50 years of clinical use, resistance to amphotericin B (AMB) among yeast species has been extremely rarely reported until recently. Reduced susceptibility to AMB (rs-AMB) among yeast species is, therefore, a matter of serious concern due to the availability of only four classes of antifungal drugs. Recent studies in Candida glabrata, Candida lusitaniae, and Candida auris have identified ERG genes involved in ergosterol biosynthesis as the major targets conferring rs-AMB. The results of this study also show that nonsynonymous mutations in ERG2 impair its function, abolish ergosterol from C. kefyr, and confer rs-AMB. Thus, rapid detection of rs-AMB among clinical isolates will help in proper management of invasive C. kefyr infections.
A phenomics approach reveals interspecific differences in integrated developmental responses to chronic elevated temperatures

ABSTRACT Phenomics, high-dimensional organismal phenotyping, is advanced as a solution to quantifying complex developmental responses to elevated temperatures. ‘Energy proxy traits’ (EPTs) measure the phenotype as a spectrum of energy values across different temporal frequencies from pixel value fluctuations of video. Although they have proven effective in measuring the biology of complex and dynamic developing organisms, their utility in assessing environmental sensitivity of different species is untested. Using EPTs, we assess the relative thermal sensitivities of embryos of three species of freshwater snail with marked differences in their developmental event timings. Embryos of Lymnaea stagnalis, Radix balthica and Physella acuta were videoed hourly for the duration of their embryonic development at two temperatures: 20°C and 25°C. The video was used to calculate EPTs for the duration of their embryonic development, and during discrete physiological windows in development. Changes in energy spectra during development identified marked differences in thermal sensitivities between species, and suggest a relatively heightened sensitivity of gross rates of embryonic physiology and behaviour in embryos of R. balthica, developmental-window-specific thermal responses that reflect ontogenetic differences in observable physiologies, and temperature-induced changes in physiological event timing. EPTs enabled comparison of high-dimensional spectral phenotypes, providing a unique capability for assessing sensitivity continuously in developing individuals. Such integrative and scalable phenotyping is a prerequisite for improved understanding of the sensitivity of early life stages of different species.
Application of cell laden hydrogels with temporally tunable stiffness in biomedical research

Extracellular matrix (ECM) is a dynamic and complex environment regulating the cell fate and behavior. It is characterized by biophysical and biochemical properties specific for each tissue. Interestingly, hydrogels can serve as exceptional artificial cellular microenvironments as they can be designed to mimic the key features of the native ECM. They are valuable tools to understand how cells respond to complex microenvironments in normal and pathologic conditions. However, unlike the highly dynamic structure of ECM, nearly all of the conventional hydrogel platforms are primarily static and lack the dynamic properties of native extracellular matrices. Thus, it is necessary to develop dynamic hydrogels to better understand the mechanisms by which dynamic changes of ECM contribute to biological processes. Stiffness is one of the significant dynamic components of ECM which must be appropriately mimicked over time in vitro. In this review, we cover recent advances in engineering strategies to make cell laden hydrogels with temporally tunable stiffness. We also highlight the applications of these hydrogel systems in biomedicine focusing on specific examples in cancer, cardiovascular system, tissue fibrosis and stem cell research. Finally, the challenges regarding the development and application of cell laden hydrogels with temporally tunable stiffness are proposed.
Magnetic field of current monopoles in prolate and oblate spheroid volume conductors

We derive an equation for the magnetic field contributed from the volume current generated by a current monopole in two special finite volume conductor shapes, i.e., prolate spheroid and oblate spheroid. In deriving the equation, fixed referential current monopoles are added to the finite system in order to balance the volume current generated by the current monopole under study. The location of these monopoles is chosen such that they produce an equipotential surface which coincides with the volume conductor and therefore do not contribute to the magnetic field. The magnetic field generated by arbitrarily distributed, but balanced, current monopoles within a prolate or oblate spheroid volume conductor can then be derived. The magnetic field generated by a current dipole in these volume conductors can then be obtained from the monopole solution and is identical to the previously derived dipole solution.
A Comparison of Host Responses to Infection with Wild-Type Avian Influenza Viruses in Chickens and Tufted Ducks

Our current findings highlight important aspects of IAV infection in birds that have implications for our understanding of its zoonotic ecology. In contrast to mallards where the intestinal tract is the main site of IAV replication, chickens and tufted ducks show limited or no signs of intestinal infection suggesting that the fecal-oral transmission route might not apply to all bird IAV host species. ABSTRACT Cross-species transmission of influenza A virus (IAV) from wild waterfowl to poultry is the first step in a chain of events that can ultimately lead to exposure and infection of humans. Herein, we study the outcome of infection with eight different mallard-origin IAV subtypes in two different avian hosts: tufted ducks and chickens. We found that infection and shedding patterns as well as innate immune responses were highly dependent on viral subtypes, host species, and inoculation routes. For example, intraoesophageal inoculation, commonly used in mallard infection experiments, resulted in no infections in contrast to oculonasal inoculation, suggesting a difference in transmission routes. Despite H9N2 being endemic in chickens, inoculation of mallard-origin H9N2 failed to cause viable infection beyond 1 day postinfection in our study design. The innate immune responses were markedly different in chickens and tufted ducks, and despite the presence of retinoic acid-inducible gene-I (RIG-I) in tufted duck transcriptomes, it was neither up nor downregulated in response to infection. Overall, we have revealed the heterogeneity of infection patterns and responses in two markedly different avian hosts following a challenge with mallard-origin IAV. These virus-host interactions provide new insights into important aspects of interspecies transmission of IAV. IMPORTANCE Our current findings highlight important aspects of IAV infection in birds that have implications for our understanding of its zoonotic ecology. In contrast to mallards where the intestinal tract is the main site of IAV replication, chickens and tufted ducks show limited or no signs of intestinal infection suggesting that the fecal-oral transmission route might not apply to all bird IAV host species. Our results indicate that mallard-origin IAVs undergo genetic changes upon introduction into new hosts, suggesting rapid adaptation to a new environment. However, similar to the mallard, chickens and tufted ducks show a limited immune response to infection with low pathogenic avian influenza viruses. These findings and future studies in different IAV hosts are important for our understanding of barriers to IAV transmission between species and ultimately from the wild reservoir to humans.
Performance of co‐culture strategy on nutrient removal and biogas upgrading by strigolactone induction

In this study, we investigated the performance and elucidated the synergistic effects of microalgae–fungi symbionts co‐cultured with 10−7 and 10−9 mol L−1 of GR24 and supplemented with endophytic bacteria, multi‐walled carbon nanotubes (MWCNTs) or vitamin B12 (VB12), on nutrient removal and biogas upgrading. The results showed that the microalgae–fungi–bacteria symbiotic system co‐cultured with 10−9 mol L−1 GR24 presented the optimal growth performance of 0.368 ± 0.04 d−1, chlorophyll a of 249.36 ± 22.31 μg L−1, and extracellular carbonic anhydrase activity of 42.55 ± 3.755 enzyme units. In this co‐culture system, the organic matter, nutrients, and CO2 purification obtained the highest removal efficiency, with 81.35 ± 7.96% for chemical oxygen demand, 83.56 ± 7.91% total nitrogen, 84.17 ± 7.95% total phosphorus, and 63.72 ± 6.06% CO2. The symbiont system also greatly increased the methane content in the biogas by 30.67%. The remarkable performance of the microalgae–fungi–bacteria symbiotic system shows its ability to be broadly applied in simultaneous biogas upgrading and wastewater treatment.
A superior linearization method for signomial discrete functions in solving three-dimensional open-dimension rectangular packing problems

ABSTRACT This article studies the three-dimensional open-dimension rectangular packing problem (3D-ODRPP) in which a set of given rectangular boxes is packed into a large container of minimal volume. This problem is usually formulated as a mixed-integer nonlinear programming problem with a signomial term in the objective. Existing exact methods experience difficulty in solving large-scale problems within a reasonable amount of time. This study reformulates the original problem as a mixed-integer linear programming problem by a novel method that reduces the number of constraints in linearizing the signomial term with discrete variables. In addition, the range reduction method is used to tighten variable bounds for further reducing the number of variables and constraints in problem transformation. Numerical experiments are presented to demonstrate that the computational efficiency of the proposed method is superior to existing methods in obtaining the global optimal solution of the 3D-ODRPP.
Experimental Models of Alcohol Use Disorder and Their Application for Pathophysiological Investigations

Alcohol use disorder (AUD) is a complex disorder characterized by compulsive alcohol use and a lack of control over alcohol intake. Several experimental methods using mouse models have been developed to improve research regarding this disorder. Mouse behavioral paradigms are advantageous in inducing alcohol dependence and evaluating alcohol intake, circumventing ethical issues, and increasing experimental control over human‐based experiments. These behavioral methods typically fall under one of two categories: forced exposure and voluntary consumption. This paper highlights two common paradigms used to study AUD in rodent models: one forced exposure method (use of a vapor inhalation system for alcohol exposure) and one voluntary consumption method (the two‐bottle choice procedure). The effectiveness and experimental validity of these behavioral paradigms for pathophysiological investigations of AUD and how they can be combined are also discussed, along with their individual strengths and weaknesses. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC.
Effect of dietary factors and time of day on iron absorption from oral iron supplements in iron deficient women

Guidelines generally recommend taking iron supplements in the morning away from meals and with ascorbic acid (AA) to increase iron absorption. However, there is little direct evidence on the effects of dietary factors and time of day on absorption from iron supplements. In iron‐depleted women (n = 34; median serum ferritin 19.4 μg/L), we administered 100 mg iron doses labeled with 54Fe, 57Fe, or 58Fe in each of six different conditions with: (1) water (reference) in the morning; (2) 80 mg AA; (3) 500 mg AA; (4) coffee; (5) breakfast including coffee and orange juice (containing ~90 mg AA); and (6) water in the afternoon. Fractional iron absorption (FIA) from these n = 204 doses was calculated based on erythrocyte incorporation of multiple isotopic labels. Compared to the reference: 80 mg AA increased FIA by 30% (p < .001) but 500 mg AA did not further increase FIA (p = .226); coffee decreased FIA by 54% (p = .004); coffee with breakfast decreased FIA by 66% (p < .001) despite the presence of ~90 mg of AA. Serum hepcidin was higher (p < .001) and FIA was 37% lower (p = .059) in the afternoon compared to the morning. Our data suggest that to maximize efficacy, ferrous iron supplements should be consumed in the morning, away from meals or coffee, and with an AA‐rich food or beverage. Compared to consuming a 100 mg iron dose in the morning with coffee or breakfast, consuming it with orange juice alone results in a ~ 4‐fold increase in iron absorption, and provides ~20 more mg of absorbed iron per dose. The trial was registered at Clinicaltrials.gov(NCT04074707).
Narrowband-ultraviolet B vs Broadband-ultraviolet B in Treatment of Chronic Pruritus: A Randomized, Single-blinded, Non-inferiority Study

Narrowband-ultraviolet B has shown increased efficacy over broadband-ultraviolet B in pruritic skin diseases, such as psoriasis and atopic dermatitis. In patients with chronic pruritus, e.g. in end-stage renal disease, broadband-ultraviolet B is recommended, but narrowband-ultraviolet B has also shown efficacy in reducing pruritus. This randomized, single blinded, non-inferiority study investigated the effects of narrowband-ultraviolet B compared with broadband-ultraviolet B. Patients with chronic pruritus were treated with either broadband- or narrowband-UVB 3 times a week for 6 weeks and clinical response was monitored. Pruritus, sleep disturbance, and the patients’ subjective overall response to treatment were evaluated by the patients on a visual analogue scale (0–10). Skin excoriations were evaluated by investigators on a 4-point scale (0–3). Both phototherapeutic modalities showed significant antipruritic activity (itch reduction 48% and 66.4%, respectively) by broadband-ultraviolet B and narrowband-ultraviolet B. Narrowband-ultraviolet B proved to be not inferior to broadband-ultraviolet B in treating pruritus in patients with chronic pruritus, assuming a 20% non-inferiority margin. SIGNIFICANCE Phototherapy is an important treatment modality in inflammatory skin diseases such as psoriasis, atopic dermatitis and cutaneous T-cell lymphoma (e.g. mycosis fungoides/Sézary syndrome). In patients with chronic pruritus, with or without pruriginous skin lesions, ultraviolet light therapy is capable of reducing pruritus. However, it remains unclear whether narrowband-ultraviolet B or broadband-ultraviolet B treatment is more effective to combat chronic pruritus. This study investigated the effects of narrowband-ultraviolet B and broadband-ultraviolet B on chronic pruritus, patients’ sleep quality and subjective treatment effects, as well as on skin excoriations. Narrowband-ultraviolet B was found to be not inferior to broadband-ultraviolet B in the treatment of patients with chronic pruritus.
New approaches in childhood asthma treatment

Purpose of review This review aims to summarize the most recent advances in asthma management, focusing on novel approaches to pediatric asthma. Recent findings In recent years, the therapeutic tools for pediatric asthma have expanded significantly for both the nonsevere and severe forms. The use of anti-inflammatory treatment, even for the mildest cases, and the withdrawal of symptomatic bronchodilation as monotherapy have been included in the most recent guidelines. Also, different biological therapies have revolutionized the therapeutical approach for severe uncontrolled asthma in children and adolescents. Summary With the expanding landscape of novel therapeutic approaches for pediatric asthma, further evidence is needed to help clinicians choose the best option for patients, particularly those with severe asthma. The identification of novel predictive biomarkers may also help pediatricians in selecting children and adolescents for innovative therapies.
Combined supplementation with Lactobacillus sp. and Bifidobacterium thermacidophilum isolated from Tibetan pigs improves growth performance, immunity, and microbiota composition in weaned piglets.

Probiotics, such as Lactobacillus and Bifidobacterium, promote growth in piglets by modulating gut microbiota composition and improving the host immune system. A strain of Lactobacillus sp. and Bifidobacterium thermacidophilum (B. thermacidophilum) were previously isolated from fresh feces of Tibetan pigs. The effects of these isolated strains on growth performance, intestinal morphology, immunity, microbiota composition, and their metabolites were evaluated in weaned piglets. Thirty crossbred piglets were selected and fed either a basal diet (CON), a basal diet supplemented with aureomycin (ANT), or a basal diet supplemented with Lactobacillus sp. and B. thermacidophilum (LB) for 28 days. The piglets in the ANT and LB groups had significantly higher body weight gain than those in the CON group (P < 0.05). Piglets in the ANT and LB groups had regularly arranged villi and microvilli in the small intestine. Furthermore, they had improved immune function, as indicated by decreased serum concentrations of inflammatory cytokines (P < 0.05), improved components of immune cells in the blood, mesenteric lymph nodes, and spleen. Additionally, metagenomic sequencing indicated a significant shift in cecal bacterial composition and alterations in microbiota functional profiles following Lactobacillus sp. and B. thermacidophilum supplementation. Metabolomic results revealed that the metabolites were also altered, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that several significantly altered metabolites were enriched in glycerophospholipid and cholesterol metabolism (P < 0.05). Furthermore, correlation analysis showed that several bacterial members were closely related to the alterations in metabolites, including Bacteroides sp. , which were negatively correlated with TG (16:0/18:0/20:4(5Z,8Z,11Z,14Z)), the metabolite that owned the highest variable importance of projection scores. Collectively, our findings suggest that combined supplementation with Lactobacillus sp. and B. thermacidophilum significantly improved the growth performance, immunity, and microbiota composition in weaned piglets, making them prospective alternatives to antibiotics in swine production.
Comparative features of calretinin, calbindin, and parvalbumin expressing interneurons in mouse and monkey primary visual and frontal cortices

Fundamental differences in excitatory pyramidal cells across cortical areas and species highlight the implausibility of extrapolation from mouse to primate neurons and cortical networks. Far less is known about comparative regional and species‐specific features of neurochemically distinct cortical inhibitory interneurons. Here, we quantified the density, laminar distribution, and somatodendritic morphology of inhibitory interneurons expressing one or more of the calcium‐binding proteins (CaBPs) (calretinin [CR], calbindin [CB], and/or parvalbumin [PV]) in mouse (Mus musculus) versus rhesus monkey (Macaca mulatta) in two functionally and cytoarchitectonically distinct regions—the primary visual and frontal cortical areas—using immunofluorescent multilabeling, stereological counting, and 3D reconstructions. There were significantly higher densities of CB+ and PV+ neurons in visual compared to frontal areas in both species. The main species difference was the significantly greater density and proportion of CR+ interneurons and lower extent of CaBP coexpression in monkey compared to mouse cortices. Cluster analyses revealed that the somatodendritic morphology of layer 2–3 inhibitory interneurons is more dependent on CaBP expression than on species and area. Only modest effects of species were observed for CB+ and PV+ interneuron morphologies, while CR+ neurons showed no difference. By contrast to pyramidal cells that show highly distinctive area‐ and species‐specific features, here we found more subtle differences in the distribution and features of interneurons across areas and species. These data yield insight into how nuanced differences in the population organization and properties of neurons may underlie specializations in cortical regions to confer species‐ and area‐specific functional capacities.