Miracle-dz/UniFAR-FTUs huggingface dataset:
Gene regulatory landscape of the sonic hedgehog locus in embryonic development

The organs of vertebrate species display a wide variety of morphology. A remaining challenge in evolutionary developmental biology is to elucidate how vertebrate lineages acquire distinct morphological features. Developmental programs are driven by spatiotemporal regulation of gene expression controlled by hundreds of thousands of cis‐regulatory elements. Changes in the regulatory elements caused by the introduction of genetic variants can confer regulatory innovation that may underlie morphological novelties. Recent advances in sequencing technology have revealed a number of potential regulatory variants that can alter gene expression patterns. However, a limited number of studies demonstrate causal dependence between genetic and morphological changes. Regulation of Shh expression is a good model to understand how multiple regulatory elements organize tissue‐specific gene expression patterns. This model also provides insights into how evolution of molecular traits, such as gene regulatory networks, lead to phenotypic novelty.
Methanolic Extract of the Herb Ononis spinosa L. Is an Antifungal Agent with no Cytotoxicity to Primary Human Cells

Ononis spinosa L. is a plant traditionally used as folk remedy. There are numerous studies regarding chemical constituents and health beneficial properties of Ononidis Radix. The following study was designed to investigate chemical composition and antifungal potential of the methanolic extract obtained from the O. spinosa L. herb. Chemical analyses regarding phenolic compounds of O. spinosa were performed by liquid chromatography with mass spectrometry (LC-DAD-ESI/MSn). Antifungal activity, antibiofilm properties and antifungal mode of action of the extract were evaluated, as well as cytotoxicity. Chemical analyses revealed the presence of flavonoids, isoflavonoids and phenolic acids in O. spinosa, with kaempherol-O-hexoside-pentoside being the most abundant compound (5.1 mg/g extract). Methanolic extract was active against all of the tested microfungi with Penicillium aurantiogriseum being the most sensitive to the extract inhibitory effect at 0.02 mg/mL; and effectively inhibited biofilms formed by Candida strains. Minimum fungicidal concentrations of extract rose in the presence of ergosterol and leakage of cellular components was detected. The extract showed no cytotoxicity to human gingival fibroblast (HGF-1) cells. This study significantly contributes to overall knowledge about medicinal potential of O. spinosa herbal extract and enlightens previously unrevealed properties. O. spinosa aerial parts seem to be an interesting candidate for the development of antifungal preparations, non-toxic to human cells.
Noninvasive Ventilation as a Weaning Strategy in Subjects with Acute Hypoxemic Respiratory Failure

BACKGROUND: Weaning through noninvasive ventilation (NIV) after early extubation may facilitate invasive ventilation withdrawal and reduce related complications in patients with hypercapnic respiratory failure. However, the effects of NIV weaning are uncertain in patients with acute hypoxemic respiratory failure (AHRF). We aimed to investigate whether NIV weaning could reduce hospital mortality and other outcomes compared with invasive weaning in subjects with hypoxemic AHRF. METHODS: We searched medical literature databases for relevant articles published from inception to February 2019. Randomized controlled trials that adopted NIV as a weaning strategy compared with invasive weaning in hypoxemic AHRF were included. The primary outcome was hospital mortality. The secondary outcomes included ICU mortality, the ICU stay, weaning time, duration of ventilation, extubation failure, and adverse events. RESULTS: Six relevant studies, which involved 718 subjects, were included. There was no significant effect of NIV weaning on hospital mortality compared with invasive weaning (risk ratio 0.94, 95% CI 0.65–1.36; P = .74), whereas there was a significant effect of NIV weaning on shortening the ICU stay (mean difference −3.95, 95% CI −6.49 to −1.40, P = .002) and on decreasing adverse events without affecting the weaning time (standardized MD −0.04, 95% CI −0.21 to 0.14; P = .68). CONCLUSIONS: The strategy of NIV weaning did not decrease hospital mortality in subjects with hypoxemic AHRF, but it did shorten the ICU lengths of stay and reduce adverse events.
Dietary caffeic acid, ferulic acid and coumaric acid supplements on cholesterol metabolism and antioxidant activity in rats

This study was designed to test the lipid-lowering and antioxidative activities of three phenolic compounds, caffeic acid, ferulic acid and coumaric acid. Four groups of rats were given a semisynthetic diet containing 3% of cholesterol for 6 weeks. The control group only received a high cholesterol diet, whereas the other three groups received a diet including 0.2% of caffeic acid, 0.2% of ferulic acid and 0.2% of coumaric acid. The caffeic acid, ferulic acid and coumaric acid significantly lowered the plasma lipid and hepatic cholesterol levels compared to those in the control (p＜0.05). The hepatic HMG-CoA reductase activity was significantly lower in the caffeic acid group than in the ferulic acid and coumaric acid groups (p＜0.05), while the hepatic ACAT activity was significantly lower in the caffeic acid, ferulic acid and coumaric acid groups compared to the control group (p＜0.05). The overall potential of the antioxidant system was significantly enhanced by the caffeic acid, ferulic acid and coumaric acid supplements as the plasma and hepatic TBARS levels were lowered while the hepatic SOD activities and GSH concentration were elevated in the high-cholesterol-fed rats (p＜0.05). Furthermore, these results indicated that the supplementation of caffeic acid, ferulic acid and coumaric acid boosted the antioxidant activity in rats and promoted the excretion of neutral sterol and acidic sterol (p＜0.05), thereby leading to a decreased absorption of dietary cholesterol as well as lower plasma, hepatic cholesterol and promoted excretion of fecal sterols.
Kokumi Taste Active Peptides Modulate Salt and Umami Taste

Kokumi taste substances exemplified by γ-glutamyl peptides and Maillard Peptides modulate salt and umami tastes. However, the underlying mechanism for their action has not been delineated. Here, we investigated the effects of a kokumi taste active and inactive peptide fraction (500–10,000 Da) isolated from mature (FIIm) and immature (FIIim) Ganjang, a typical Korean soy sauce, on salt and umami taste responses in humans and rodents. Only FIIm (0.1–1.0%) produced a biphasic effect in rat chorda tympani (CT) taste nerve responses to lingual stimulation with 100 mM NaCl + 5 μM benzamil, a specific epithelial Na+ channel blocker. Both elevated temperature (42 °C) and FIIm produced synergistic effects on the NaCl + benzamil CT response. At 0.5% FIIm produced the maximum increase in rat CT response to NaCl + benzamil, and enhanced salt taste intensity in human subjects. At 2.5% FIIm enhanced rat CT response to glutamate that was equivalent to the enhancement observed with 1 mM IMP. In human subjects, 0.3% FIIm produced enhancement of umami taste. These results suggest that FIIm modulates amiloride-insensitive salt taste and umami taste at different concentration ranges in rats and humans.
Predicting cell lineages using autoencoders and optimal transport

Lineage tracing involves the identification of all ancestors and descendants of a given cell, and is an important tool for studying biological processes such as development and disease progression. However, in many settings, controlled time-course experiments are not feasible, for example when working with tissue samples from patients. Here we present ImageAEOT, a computational pipeline based on autoencoders and optimal transport for predicting the lineages of cells using time-labeled datasets from different stages of a cellular process. Given a single-cell image from one of the stages, ImageAEOT generates an artificial lineage of this cell based on the population characteristics of the other stages. These lineages can be used to connect subpopulations of cells through the different stages and identify image-based features and biomarkers underlying the biological process. To validate our method, we apply ImageAEOT to a benchmark task based on nuclear and chromatin images during the activation of fibroblasts by tumor cells in engineered 3D tissues. We further validate ImageAEOT on chromatin images of various breast cancer cell lines and human tissue samples, thereby linking alterations in chromatin condensation patterns to different stages of tumor progression. Our results demonstrate the promise of computational methods based on autoencoding and optimal transport principles for lineage tracing in settings where existing experimental strategies cannot be used.
Ultrasound-Enhanced Chemo-Photodynamic Combination Therapy by Using Albumin "Nanoglue"-Based Nanotheranostics.

The combination of photodynamic therapy (PDT) and chemotherapy is considered to enhance the antitumor immunity and combat multidrug resistance. Some preclinical studies have reported a positive therapeutic outcome of using ultrasound (US) irradiation to enhance chemotherapy, but the combination of these three modalities have yet to be investigated. Inspired by the discovery of a strong affinity between a photosensitizer sinoporphyrin sodium (DVDMS) and human serum albumin (HSA), a clinically used albumin-paclitaxel (HSA-PTX) nanoparticle is utilized as a "nanoglue" to load a large amount of DVDMS by simple mixing. The five conformations of HSA and DVDMS with highest affinity were calculated using AutoDock Vina. The obtained albumin "nanoglue"-based nanotheranostics, HSA-PTX-DVDMS (HPD), has better fluorescence imaging and PDT performance than free DVDMS, probably due to the less quenching of DVDMS after dispersion in albumin. An efficacious tumor-targeting enhancement of chemotherapy by US irradiation is verified in a bilateral subcutaneous 4T1 tumors model. With the aid of US irradiation, the combined PDT and chemotherapy mediated by HPD achieve effective tumor growth inhibition. Overall, this "nanoglue"-based nanotheranostics is composed of several clinically used elements and integrates three clinical modalities with application prospects in clinic.
Computed tomography and cross‐sectional anatomy of the head in the red fox (Vulpes vulpes)

The red fox (Vulpes vulpes) is a universally widespread wild carnivore in the world. It has an important impact on human interests and plays a vital role in conservation biology. There is no report to describe computed tomography (CT) of the red fox head and its correlation with gross anatomy. Therefore, the intent of the present study was to document, by CT, the basic anatomical structures in the head region of the red fox to lay the groundwork of an appropriate anatomical description of the head structures comparable with traditional dissection technique. Three red fox heads were imaged sagittally and transversely using CT scanner. Six red fox heads were then serially cut, sagittally and transversely, by an electric band saw, and the obtained slices were cleaned and photographed. Different anatomical structures on CT images and the corresponding anatomic sections were identified and labelled. CT images revealed an excellent three‐dimensional definition of bony structures of the entire craniofacial region. Moreover, CT scans revealed different contrasts between bones, oral and nasal cavities, paranasal sinuses and pharynx which enabled good visualization of those structures. The paranasal sinus system in red fox was poorly developed and represented by a frontal sinus and a small sphenoid sinus, in addition to a maxillary recess. In conclusion, the series of CT images of the normal red fox head presented in the current study will serve as an anatomical reference for the normal head of the red fox, which in turn will improve knowledge for clinical interpretation.
Robust Atomistic Modeling of Materials, Organometallic, and Biochemical Systems

Abstract Modern chemistry seems to be unlimited in molecular size and elemental composition. Metal‐organic frameworks or biological macromolecules involve complex architectures and a large variety of elements. Yet, a general and broadly applicable theoretical method to describe the structures and interactions of molecules beyond the 1000‐atom size regime semi‐quantitatively is not self‐evident. For this purpose, a generic force field named GFN‐FF is presented, which is completely newly developed to enable fast structure optimizations and molecular‐dynamics simulations for basically any chemical structure consisting of elements up to radon. The freely available computer program requires only starting coordinates and elemental composition as input from which, fully automatically, all potential‐energy terms are constructed. GFN‐FF outperforms other force fields in terms of generality and accuracy, approaching the performance of much more elaborate quantum‐mechanical methods in many cases.
Thermogenesis in Adipose Tissue Activated by Thyroid Hormone

Thermogenesis is the production of heat that occurs in all warm-blooded animals. During cold exposure, there is obligatory thermogenesis derived from body metabolism as well as adaptive thermogenesis through shivering and non-shivering mechanisms. The latter mainly occurs in brown adipose tissue (BAT) and muscle; however, white adipose tissue (WAT) also can undergo browning via adrenergic stimulation to acquire thermogenic potential. Thyroid hormone (TH) also exerts profound effects on thermoregulation, as decreased body temperature and increased body temperature occur during hypothyroidism and hyperthyroidism, respectively. We have termed the TH-mediated thermogenesis under thermoneutral conditions “activated” thermogenesis. TH acts on the brown and/or white adipose tissues to induce uncoupled respiration through the induction of the uncoupling protein (Ucp1) to generate heat. TH acts centrally to activate the BAT and browning through the sympathetic nervous system. However, recent studies also show that TH acts peripherally on the BAT to directly stimulate Ucp1 expression and thermogenesis through an autophagy-dependent mechanism. Additionally, THs can exert Ucp1-independent effects on thermogenesis, most likely through activation of exothermic metabolic pathways. This review summarizes thermogenic effects of THs on adipose tissues.
Fracture Resistance of Zirconia-Reinforced Lithium Silicate Ceramic Crowns Cemented with Conventional or Adhesive Systems: An In Vitro Study

In recent years, Zirconia-reinforced Lithium Silicate ceramic (ZLS), combining lithium-silicate and zirconia features, has shown to have excellent mechanical and aesthetic characteristics. Thus, the aim of this study was to compare the fracture strength of ZLS single crowns cemented with two different cementation techniques. Twenty crowns were realised and cemented on teeth replicas achieved from an extracted premolar human tooth. The samples were divided into two groups of 10 specimens each, Glass-ionomeric cement (GIC) group and Self-Adhesive Resin Cement (ARC) group. The mechanical test was performed using a universal testing machine. The specimens were then evaluated with a scanning electron microscope (SEM) to identify for all crowns and related abutments the pattern of fracture after the breaking point. The data obtained were statistically analysed. The mean fracture toughness values and standard deviations (±SD) were 2227 ± 382 N and 3712 ± 319 N respectively for GIC and ARC groups. In fact, t-test showed a statistically significant difference between the two groups (p < 0.001). Moreover, the SEM results demonstrated portions of abutments still attached to the crown fragments in the ARC group, whilst these were not present in the GIC group. Within the limitations of this study, these results suggest the use of adhesive cementation for ZLS crowns, which significantly increase the compressive strength of ZLS restorations compared to GIC.
A doubly auxotrophic CHO‐K1 cell line for the production of recombinant monoclonal antibodies

Chinese hamster ovary (CHO) cells are the most widely used mammalian hosts for recombinant protein production due to their hardiness, ease of transfection, and production of glycan structures similar to those in natural human monoclonal antibodies. To enhance the usefulness of CHO‐K1 cells we developed a new selection system based on double auxotrophy. We used CRISPR‐Cas9 to knockout the genes that encode the bifunctional enzymes catalyzing the last two steps in the de novo synthesis of pyrimidines and purines (uridine monophosphate synthase and 5‐aminoimidazole‐4‐carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase [ATIC], respectively). Survival of these doubly auxotrophic cells depends on the provision of sources of purines and pyrimidines or on the transfection and integration of open reading frames encoding these two enzymes. We successfully used one such double auxotroph (UA10) to select for stable transfectants carrying (a) the recombinant tumor necrosis factor‐α receptor fusion protein etanercept and (b) the heavy and light chains of the anti‐Her2 monoclonal antibody trastuzumab. Transfectant clones produced these recombinant proteins in a stable manner and in substantial amounts. The availability of this double auxotroph provides a rapid and efficient selection method for the serial or simultaneous transfer of genes for multiple polypeptides of choice into CHO cells using readily available purine‐ and pyrimidine‐free commercial media.
Mechanisms of Lifespan Regulation by Calorie Restriction and Intermittent Fasting in Model Organisms

Genetic and pharmacological interventions have successfully extended healthspan and lifespan in animals, but their genetic interventions are not appropriate options for human applications and pharmacological intervention needs more solid clinical evidence. Consequently, dietary manipulations are the only practical and probable strategies to promote health and longevity in humans. Caloric restriction (CR), reduction of calorie intake to a level that does not compromise overall health, has been considered as being one of the most promising dietary interventions to extend lifespan in humans. Although it is straightforward, continuous reduction of calorie or food intake is not easy to practice in real lives of humans. Recently, fasting-related interventions such as intermittent fasting (IF) and time-restricted feeding (TRF) have emerged as alternatives of CR. Here, we review the history of CR and fasting-related strategies in animal models, discuss the molecular mechanisms underlying these interventions, and propose future directions that can fill the missing gaps in the current understanding of these dietary interventions. CR and fasting appear to extend lifespan by both partially overlapping common mechanisms such as the target of rapamycin (TOR) pathway and circadian clock, and distinct independent mechanisms that remain to be discovered. We propose that a systems approach combining global transcriptomic, metabolomic, and proteomic analyses followed by genetic perturbation studies targeting multiple candidate pathways will allow us to better understand how CR and fasting interact with each other to promote longevity.
Testing the Preliminary Validity of a Multidimensional Framework for Studying the Effects of Cancer Health Literacy on Cancer Screening Behaviors among Diverse Populations

The objective of this study was to evaluate the applicability of a multidimensional framework to explore factors associated with cancer literacy and its effects on receiving cancer screenings among diverse populations. Based on the conceptual framework, we developed and pilot-tested the Multidimensional Cancer Literacy Questionnaire (MCLQ) among 1500 individuals (African Americans, Latinos and Whites) in Louisiana. Exploratory factor analysis was used to identify the MCLQ underlying structure and predominant factors explaining each of the dimensions in the model. A total of 82 items (explaining 67% of the total variance) in the MCLQ were grouped into 20 factors associated with three key dimensions related to cancer literacy. Preliminary validity of the MCLQ was supported: Cronbach alpha for the scale score was 0.89 and internal consistency reliability coefficients for each factor were all above 0.67. The Facilitators Domain included five factors (28 items) that may positively influence individuals to have early-detection cancer screenings. The Barriers Domain included seven factors (26 items) explaining aspects that may negatively influence individuals to have cancer screenings. The Cultural Domain included eight factors (28 items) related to aspects that influence positively or negatively individuals’ perceptions regarding cancer as a disease, screenings and treatments. A multidimensional framework to study cancer literacy, including cultural attitudes, beliefs and practices, as well as facilitators and barriers, among diverse populations, will increase understanding of factors influencing individuals’ approach to cancer prevention and screening. Results will inform further testing of the multidimensional framework and questionnaire.
Detection of group A bovine rotavirus in diarrhoeic calves by reverse transcriptase polymerase chain reaction (RT-PCR) and electropherotyping.

In the present study, reverse transcription polymerase chain reaction (RT-PCR) was standardized and applied for detection of bovine rotavirus A (BRA) in diarrhoeic clinical samples (n=112) collected from dairy farms of Bareilly (Uttar Pradesh) and Nammakkal (Tamil Nadu) regions, India. The presence of virus was also confirmed by electropherotyping analysis. For RT-PCR, two pairs of published primers were used for amplification of VP6 and VP7 gene of group A rotavirus. BRA RNA extracted from faecal samples and infected MDBK cells by TRIzol LS method was used for RT-PCR detection of the virus and electropherotyping. RT-PCR amplification yielded virus specific amplicons of 309 bp and 304 bp sizes for VP6 and VP7 gene, respectively. Out a total of 112 clinical samples rotavirus RNA was detected in 27 (24.11%) samples. Electrophoretic analysis of rotavirus dsRNA segments yielded 4-2-3-2 long electrophoretic segmental pattern for bovine rotavirus group A. The molecular tool of RT-PCR and electropherotyping were found suitable for detection of bovine rotavirus group A and could be well applied for rapid detection of rotaviruses in clinical/field samples.
Generation and validation of structurally defined antibody–siRNA conjugates

Abstract Gene silencing by RNA interference (RNAi) has emerged as a powerful treatment strategy across a potentially broad range of diseases. Tailoring siRNAs to silence genes vital for cancer cell growth and function could be an effective treatment, but there are several challenges which must be overcome to enable their use as a therapeutic modality, among which efficient and selective delivery to cancer cells remains paramount. Attempts to use antibodies for siRNA delivery have been reported but these strategies use either nonspecific conjugation resulting in mixtures, or site-specific methods that require multiple steps, introduction of mutations, or use of enzymes. Here, we report a method to generate antibody–siRNA (1:2) conjugates (ARCs) that are structurally defined and easy to assemble. This ARC platform is based on engineered dual variable domain (DVD) antibodies containing a natural uniquely reactive lysine residue for site-specific conjugation to β-lactam linker-functionalized siRNA. The conjugation is efficient, does not compromise the affinity of the parental antibody, and utilizes chemically stabilized siRNA. For proof-of-concept, we generated DVD-ARCs targeting various cell surface antigens on multiple myeloma cells for the selective delivery of siRNA targeting β-catenin (CTNNB1). A set of BCMA-targeting DVD-ARCs at concentrations as low as 10 nM revealed significant CTNNB1 mRNA and protein knockdown.