Miracle-dz/UniFAR-FTUs huggingface dataset:
Long-Distance Effects of H-NS Binding in the Control of hilD Expression in the Salmonella SPI1 Locus

Members of the foodborne pathogen Salmonella rely on a type III secretion system to invade intestinal epithelial cells and initiate infection. This system was acquired through horizontal gene transfer, essentially creating the Salmonella genus. ABSTRACT Salmonella enterica serovar Typhimurium utilizes a type three secretion system (T3SS) carried on the Salmonella pathogenicity island 1 (SPI1) to invade intestinal epithelial cells and induce inflammatory diarrhea. HilA activates expression of the T3SS structural genes. Expression of hyper invasion locus A (hilA) is controlled by the transcription factors HilD, HilC, and RtsA, which act in a complex feed-forward regulatory loop. The nucleoid-associated protein H-NS is a xenogeneic silencer that has a major effect on SPI1 expression. In this work, we use genetic techniques to show that disruptions of the chromosomal region surrounding hilD have a cis effect on H-NS-mediated repression of the hilD promoter; this effect occurs asymmetrically over ∼4 kb spanning the prgH-hilD intergenic region. CAT cassettes inserted at various positions in this region are also silenced in relation to the proximity to the hilD promoter. We identify a putative H-NS nucleation site, and its mutation results in derepression of the locus. Furthermore, we genetically show that HilD abrogates H-NS-mediated silencing to activate the hilD promoter. In contrast, H-NS-mediated repression of the hilA promoter, downstream of hilD, is through its control of HilD, which directly activates hilA transcription. Likewise, activation of the prgH promoter, although in a region silenced by H-NS, is strictly dependent on HilA. In summary, we propose a model in which H-NS nucleates within the hilD promoter region to polymerize and exert its repressive effect. Thus, H-NS-mediated repression of SPI1 is primarily through the control of hilD expression, with HilD capable of overcoming H-NS to autoactivate. IMPORTANCE Members of the foodborne pathogen Salmonella rely on a type III secretion system to invade intestinal epithelial cells and initiate infection. This system was acquired through horizontal gene transfer, essentially creating the Salmonella genus. Expression of this critical virulence factor is controlled by a complex regulatory network. The nucleoid protein H-NS is a global repressor of horizontally acquired genomic loci. Here, we identify the critical site of H-NS regulation in this system and show that alterations to the DNA over a surprisingly large region affect this regulation, providing important information regarding the mechanism of H-NS action.
Current therapeutic approaches in the management of hemophilia—a consensus view by the Romanian Society of Hematology

Hemophilia A (HA) and hemophilia B (HB) are rare disorders, being caused by the total lack or under-expression of two factors from the coagulation cascade coded by genes of the X chromosome. Thus, in hemophilic patients, the blood does not clot properly. This results in spontaneous bleeding episodes after an injury or surgical intervention. A patient-centered regimen is considered optimal. Age, pharmacokinetics, bleeding phenotype, joint status, adherence, physical activity, personal goals are all factors that should be considered when individualizing therapy. In the past 10 years, many innovations in the diagnostic and treatment options were presented as being either approved or in development, thus helping clinicians to improve the standard-of-care for patients with hemophilia. Recombinant factors still remain the standard of care in hemophilia, however they pose a challenge to treatment adherence because they have short half-life, which where the extended half-life (EHL) factors come with the solution, increasing the half-life to 96 hours. Gene therapies have a promising future with proven beneficial effects in clinical trials. We present and critically analyze in the current manuscript the pros and cons of all the major discoveries in the diagnosis and treatment of HA and HB, as well as identify key areas of hemophilia research where improvements are needed.
Mechanism of transcription initiation and primer generation at the mitochondrial replication origin OriL

The intricate process of human mtDNA replication requires the coordinated action of both transcription and replication machineries. Transcription and replication events at the lagging strand of mtDNA prompt the formation of a stem‐loop structure (OriL) and the synthesis of a ∼25 nt RNA primer by mitochondrial RNA polymerase (mtRNAP). The mechanisms by which mtRNAP recognizes OriL, initiates transcription, and transfers the primer to the replisome are poorly understood. We found that transcription initiation at OriL involves slippage of the nascent transcript. The transcript slippage is essential for initiation complex stability and its ability to translocate the mitochondrial DNA polymerase gamma, PolG, which pre‐binds to OriL, downstream of the replication origin thus allowing for the primer synthesis. Our data suggest the primosome assembly at OriL—a complex of mtRNAP and PolG—can efficiently generate the primer, transfer it to the replisome, and protect it from degradation by mitochondrial endonucleases.
Matching Biomedical Ontologies: Construction of Matching Clues and Systematic Evaluation of Different Combinations of Matchers

Background Ontology matching seeks to find semantic correspondences between ontologies. With an increasing number of biomedical ontologies being developed independently, matching these ontologies to solve the interoperability problem has become a critical task in biomedical applications. However, some challenges remain. First, extracting and constructing matching clues from biomedical ontologies is a nontrivial problem. Second, it is unknown whether there are dominant matchers while matching biomedical ontologies. Finally, ontology matching also suffers from computational complexity owing to the large-scale sizes of biomedical ontologies. Objective To investigate the effectiveness of matching clues and composite match approaches, this paper presents a spectrum of matchers with different combination strategies and empirically studies their influence on matching biomedical ontologies. Besides, extended reduction anchors are introduced to effectively decrease the time complexity while matching large biomedical ontologies. Methods In this paper, atomic and composite matching clues are first constructed in 4 dimensions: terminology, structure, external knowledge, and representation learning. Then, a spectrum of matchers based on a flexible combination of atomic clues are designed and utilized to comprehensively study the effectiveness. Besides, we carry out a systematic comparative evaluation of different combinations of matchers. Finally, extended reduction anchor is proposed to significantly alleviate the time complexity for matching large-scale biomedical ontologies. Results Experimental results show that considering distinguishable matching clues in biomedical ontologies leads to a substantial improvement in all available information. Besides, incorporating different types of matchers with reliability results in a marked improvement, which is comparative to the state-of-the-art methods. The dominant matchers achieve F1 measures of 0.9271, 0.8218, and 0.5 on Anatomy, FMA-NCI (Foundation Model of Anatomy-National Cancer Institute), and FMA-SNOMED data sets, respectively. Extended reduction anchor is able to solve the scalability problem of matching large biomedical ontologies. It achieves a significant reduction in time complexity with little loss of F1 measure at the same time, with a 0.21% decrease on the Anatomy data set and 0.84% decrease on the FMA-NCI data set, but with a 2.65% increase on the FMA-SNOMED data set. Conclusions This paper systematically analyzes and compares the effectiveness of different matching clues, matchers, and combination strategies. Multiple empirical studies demonstrate that distinguishing clues have significant implications for matching biomedical ontologies. In contrast to the matchers with single clue, those combining multiple clues exhibit more stable and accurate performance. In addition, our results provide evidence that the approach based on extended reduction anchors performs well for large ontology matching tasks, demonstrating an effective solution for the problem.
Development of a novel polymer-based carrier for deformable liposomes for the controlled dermal delivery of naringenin

Abstract In recent years, the incidence of skin cancer has increased worldwide, presenting a significant burden on healthcare services. Chemotherapy intervention is often not appropriate for all patients due to localized adverse effects on skin physiology. The aim of this study was, therefore, to consider the development of a novel phytochemical-based deformable liposomal formulation suspended in an aqueous gel for the controlled-release of naringenin. Naringenin is an antioxidant, free radical scavenger, anti-inflammatory agent, and immune system modulator thus may be potentially useful as a pharmacological anti-cancer agent. Formulated liposomes incorporating an increasing loading of Tween 20 (from 0% w/w to 10% w/w) demonstrated a significant decrease in deformability index (DI) (80.71 ± 2.02–59.17 ± 4.42 %), indicating an increase in elasticity. The release of naringenin over 24 h was directly affected by Tween-20 concentration, decreasing from 100.72%±4.98% to 79.53%±3.68% for 0% and 2% w/w Tween 20, respectively. Further, the incorporation of deformable liposomes into hydroxyethylcellulose (HEC) and hydroxypropyl methylcellulose (HPMC) gels resulting in a further retardation of naringenin release, 23.21%±1.17% and 19.83%±1.50%, respectively, over 24 h. Incubation of 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate-loaded liposomes with human dermal fibroblast (HDF) and keratinocyte cells demonstrated intracellular accumulation within 2 h, confirming deformable liposomes may be beneficial in improving drug penetration across dermal cells and would be valuable in emerging controlled-release formulations.
Zenkeramide: a new iso-benzofuranone propanamide and urease inhibitory constituents of Celtis zenkeri Engl stem bark (Ulmaceae)

Abstract A new iso-benzofuranone propanamide: 3-(3-oxo-1, 3-dihydroisobenzofuran-1-yl) propanamide (zenkeramide) (1) along with three known compounds: Trans-N-coumaroyltyramine (2), β-Sitosterol (3) and β-sitosterol-3-0-β-D-glucopyranoside (4) were isolated from the ethyl acetate fraction of the stem-bark of Celtis zenkeri Engl (Ulmaceae). The structure of the new compound was elucidated by extensive spectroscopic analysis. The compounds were examined for Urease Inhibitory Activity. Compounds 1 and 2 showed moderate activities (IC50 values (μM) of 42.3 ± 0.19 and 45.2 ± 0.55, respectively), while compounds 3 and 4 were potent inhibitors of the Jack bean urease (IC50 values (μM) of 20.3 ± 0.37and 27.6 ± 0.52, respectively), when compared to the standard inhibitor (thiourea- IC50 21.5 ± 0.47). The isolation of all the compounds from C. zenkeri and the urease activity of compounds 1 and 2 are reported for the first time. Graphical abstract
Identification of the blue light intensity administered to one eye required to suppress bovine plasma melatonin and investigation into effects on milk production in grazing dairy cows.

Long-day photoperiod is known to positively affect milk production in confinement dairy systems, and it has been hypothesized that pineal melatonin (MT) secretion plays a substantial role in this process. Specialized mammalian photoreceptors that regulate MT secretion are optimally stimulated by short wavelength blue light. We investigated the blue light intensity administered to one eye required to suppress MT secretion in nonlactating dairy cows, and subsequently examined effects on milk production in grazing dairy cows. Following a 14-d light-dark 8:16 h environmental conditioning period, 5 nonlactating Holstein-Friesian cows were exposed to treatments of <1, 70, 125, 175, and 225 lx for 8 additional hours using a 5 × 5 Latin square design. Light was administered via headpieces fitted with light-emitting diodes emitting blue light (465 nm) to the right eye. All cows were then exposed to a light-dark 16:8 h cycle for one night via the indoor lighting system (>200 lx white light). Plasma samples collected at regular intervals were assayed for MT. A dose-dependent effect of light treatment on mean circulating MT concentrations (and 95% CI) was observed [9.4 (7.2, 12.3), 5.0 (3.8, 6.6), 4.4 (3.3, 5.7), 3.3 (2.5, 4.3) and 1.7 (1.3, 2.3) ng/mL for treatments of 0, 70, 125, 175, and 225 lx, respectively. Only the 225 lx treatment acutely suppressed plasma melatonin concentration to levels similar to the light-dark 16:8 h treatment [1.9 (1.4, 2.5) ng/mL]. Forty spring-calving cows were blocked on parity, calving date and Economic Breeding Index for milk production and assigned to the control treatment or blue light to a single eye (LT) treatment from calving through 32 wk of lactation. The cows assigned to LT treatment were fitted with headpieces providing 225 lx of blue light to the right eye from 1700 until 0000 h. Mean milk production (and 95% CI) during 32 wk of lactation was not affected by treatment [20.3 (19.3, 21.3) vs. 20.9 (19.8, 22.0) kg/d, control and LT, respectively]. Within multiparous cows, a treatment by week interaction was detected, whereby LT treatment increased milk production during the first 12 wk of lactation [25.8 (24.3, 27.3) vs. 28.0 (26.5, 29.5) kg/d; +8.5%], but had no effect thereafter. Treatment did not affect plasma insulin-like growth factor 1. We identified the blue light intensity to one eye required to acutely suppress MT concentrations. Transient favorable effects on milk production were observed in multiparous cows. It remains unclear how single-eye blue light treatment affects galactopoiesis in grazing dairy cows, and further research is needed to explore whether this modality of light delivery represents a useful means to aid productivity in pasture-based dairy systems.
Lee Jaffe’s Unifying Approach to Psychoanalysis

Lee Jaffe’s presidential plenary paper demonstrates his career-long emphasis on unifying psychoanalysis and its theories. His use of Freud’s various technical concepts to make psychoanalytic theory applicable to talking psychotherapies of all kinds, analytic and nonanalytic, is a notable achievement and a useful pedagogical tool. By valuing common ground and unification, he aligns himself with luminaries such as Wallerstein and Rangell, who had similar goals. In keeping with these values, I offer a schematic outline of what the sort of integrated model valued by Jaffe might include.
Longitudinal Relationships Between Subjective Cognitive Decline and Objective Memory: Depressive Symptoms Mediate Between-Person Associations.

BACKGROUND Subjective cognitive decline (SCD) may be an early indicator of cognitive impairment, but depressive symptoms can confound this relationship. Associations may be influenced by differences between individuals (i.e., between-persons) or how each individual changes in their experiences over time (i.e., within-persons). OBJECTIVE We examined depressive symptoms as a mediator of the between- and within-person associations of SCD and objective memory in older adults. METHODS Coordinated analyses were conducted across four datasets drawn from large longitudinal studies. Samples (range: n = 1,889 to n = 15,841) included participants 65 years of age or older with no dementia at baseline. We used multilevel structural equation modeling to examine the mediation of SCD and objective memory through depressive symptoms, as well as direct relationships among SCD, objective memory, and depressive symptoms. RESULTS Older adults who were more likely to report SCD had lower objective memory on average (between-person associations), and depressive symptoms partially mediated this relationship in three of four datasets. However, changes in depressive symptoms did not mediate the relationship between reports of SCD and declines in objective memory in three of four datasets (within-person associations). CONCLUSION Individual differences in depressive symptoms, and not changes in an individual's depressive symptoms over time, partially explain the link between SCD and objective memory. Older adults with SCD and depressive symptoms may be at greater risk for poor cognitive outcomes. Future research should explore how perceived changes in memory affect other aspects of psychological well-being, and how these relationships influence cognitive decline and Alzheimer's disease risk.
Measuring sodium intake: research and clinical applications

Although most current guidelines recommend a daily sodium intake of less than 2.3 g/day, most people do not have a reliable estimate of their usual sodium intake. In this review, we describe the different methods used to estimate sodium intake and discuss each method in the context of specific clinical or research questions. We suggest the following classification for sodium measurement methods: preingestion measurement (controlled intake), peri-ingestion measurement (concurrent), and postingestion measurement. On the basis of the characteristics of the available tools, we suggest that: validated 24-h recall methods are a reasonable approach to estimate sodium intake in large epidemiologic studies and individual clinical counselling sessions, methods (such as single 24-h urine collection, single-time urine collection, or 24-h recall methods), are of value in population-level estimation of mean sodium intake, but are less suited for individual level estimation and a feeding-trial design using a controlled diet is the most valid and reliable method for establishing the effect of reducing sodium to a specific intake target in early phase clinical trials. By considering the various approaches to sodium measurement, investigators and public health practitioners may be better informed in assessing the health implications of sodium consumption at the individual and population level.
On the steady-state drop size distribution in stirred vessels. Part I: effect of dispersed phase viscosity

Previous studies on emulsification have used the maximum drop size (dmax) or Sauter mean diameter (d32) to investigate the effect of viscosity on the drop size distribution (DSD), however these parameters fall short for highly polydispersed emulsions. In this investigation (Part I) we studied the steady-state DSD of dilute emulsions using of silicon oils with viscosities varying across 6 orders of magnitude at different stirring speeds. Different emulsification regimes were identified; our modelling and analysis is centred on the intermediate viscosity range where interfacial cohesive stresses can be considered negligible and drop size increases with viscosity. The bimodal frequency distributions by volume were well described using two log-normal density functions. In Part II we expanded this study by using other continuous phases of different viscosity while keeping the Power number constant, thus examining the effects of viscosity ratio.
Lung nodule malignancy classification with weakly supervised explanation generation

Abstract. Purpose: Explainable AI aims to build systems that not only give high performance but also are able to provide insights that drive the decision making. However, deriving this explanation is often dependent on fully annotated (class label and local annotation) data, which are not readily available in the medical domain. Approach: This paper addresses the above-mentioned aspects and presents an innovative approach to classifying a lung nodule in a CT volume as malignant or benign, and generating a morphologically meaningful explanation for the decision in the form of attributes such as nodule margin, sphericity, and spiculation. A deep learning architecture that is trained using a multi-phase training regime is proposed. The nodule class label (benign/malignant) is learned with full supervision and is guided by semantic attributes that are learned in a weakly supervised manner. Results: Results of an extensive evaluation of the proposed system on the LIDC-IDRI dataset show good performance compared with state-of-the-art, fully supervised methods. The proposed model is able to label nodules (after full supervision) with an accuracy of 89.1% and an area under curve of 0.91 and to provide eight attributes scores as an explanation, which is learned from a much smaller training set. The proposed system’s potential to be integrated with a sub-optimal nodule detection system was also tested, and our system handled 95% of false positive or random regions in the input well by labeling them as benign, which underscores its robustness. Conclusions: The proposed approach offers a way to address computer-aided diagnosis system design under the constraint of sparse availability of fully annotated images.
Arginase-1 and P-glycoprotein are downregulated in canine hepatocellular carcinoma

Background Hepatocellular carcinoma is the most common primary hepatic malignancy in humans and dogs. Several differentially expressed molecules have been studied and reported in human hepatocellular carcinoma and non-neoplastic liver lesions. However, studies on the features of canine hepatocellular carcinoma are limited, especially related to the differential characteristics of neoplastic and non-neoplastic lesions. Objectives The study's objective was 1) to examine and evaluate the expression of arginase-1, P-glycoprotein, and cytokeratin 19 in canine liver tissues and 2) to investigate the differential features of hepatocellular carcinomas, liver tissue with non-neoplastic lesions, and paracancerous liver tissues in dogs. Methods The expression levels of three markers underwent immunohistochemical analysis in 40 non-neoplastic liver tissues, 32 hepatocellular carcinoma tissues, and 11 paracancerous liver tissues. Scoring of each marker was performed semi-quantitatively. Results Arginase-1 and P-glycoprotein were significantly downregulated in hepatocellular carcinoma, compared with hepatic tissues with non-neoplastic diseases (p < 0.001). Expression levels of arginase-1 and P-glycoprotein were also significantly lower in hepatocellular carcinoma than in paracancerous liver tissues (arginase-1, p = 0.0195; P-glycoprotein, p = 0.047). Few cytokeratin 19-positive hepatocytes were detected and only in one hepatocellular carcinoma and one cirrhotic liver sample. Conclusions The results of this study suggest that downregulation of arginase-1 and P-glycoprotein is a feature of canine hepatocellular carcinoma; thus, those markers are potential candidates for use in differentiating hepatocellular carcinomas from non-neoplastic liver lesions in dogs.
Modulation of H3.3 chromatin assembly by PML: A way to regulate epigenetic inheritance

Although the promyelocytic leukemia (PML) protein is renowned for regulating a wide range of cellular processes and as an essential component of PML nuclear bodies (PML‐NBs), the mechanisms through which it exerts its broad physiological impact are far from fully elucidated. Here, we review recent studies supporting an emerging view that PML's pleiotropic effects derive, at least partially, from its role in regulating histone H3.3 chromatin assembly, a critical epigenetic mechanism. These studies suggest that PML maintains heterochromatin organization by restraining H3.3 incorporation. Examination of PML's contribution to H3.3 chromatin assembly in the context of the cell cycle and PML‐NB assembly suggests that PML represses heterochromatic H3.3 deposition during S phase and that transcription and SUMOylation regulate PML's recruitment to heterochromatin. Elucidating PML’ s contributions to H3.3‐mediated epigenetic regulation will provide insight into PML's expansive influence on cellular physiology and open new avenues for studying oncogenesis linked to PML malfunction.