Miracle-dz/UniFAR-FTUs huggingface dataset:
Interaction Modes of Microsomal Cytochrome P450s with Its Reductase and the Role of Substrate Binding

The activity of microsomal cytochromes P450 (CYP) is strictly dependent on the supply of electrons provided by NADPH cytochrome P450 oxidoreductase (CPR). The variant nature of the isoform-specific proximal interface of microsomal CYPs implies that the interacting interface between the two proteins is degenerated. Recently, we demonstrated that specific CPR mutations in the FMN-domain (FD) may induce a gain in activity for a specific CYP isoform. In the current report, we confirm the CYP isoform dependence of CPR’s degenerated binding by demonstrating that the effect of four of the formerly studied FD mutants are indeed exclusive of a specific CYP isoform, as verified by cytochrome c inhibition studies. Moreover, the nature of CYP’s substrate seems to have a modulating role in the CPR:CYP interaction. In silico molecular dynamics simulations of the FD evidence that mutations induces very subtle structural alterations, influencing the characteristics of residues formerly implicated in the CPR:CYP interaction or in positioning of the FMN moiety. CPR seems therefore to be able to form effective interaction complexes with its structural diverse partners via a combination of specific structural features of the FD, which are functional in a CYP isoform dependent manner, and dependent on the substrate bound.
Re‐equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction

Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated CD38 NADase and reduced poly(ADP‐ribose) polymerase and SIRT1 activities, respectively, affecting many associated biological pathways. Supplementation with the NAD precursor, nicotinamide riboside, and CD38 inhibition improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence of DC fibroblasts. These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short and underscore its relevance to the pathophysiology and interventions of human telomere‐driven diseases.
Immunohistochemical localization of aquaporin 4 (AQP4) in the porcine gastrointestinal tract

The water channel aquaporin-4 (AQP4) is a protein widely expressed on plasma membrane of a variety of epithelial cells. In this study we investigated the expression of AQP4 in the gastrointestinal tract of the pig using immunohistochemical staining. We found no presence of AQP4 in the different regions of the pig stomach. In the porcine small intestine moderate immunoreactivity to AQP4 was detected in enterocytes (along the villi and in the bottom of the crypts), duodenal Brunner’s glands and in enteric ganglia in cells lying in close vicinity to myenteric as well as submucous neurons. In superficial epithelial cells of the colonic mucosa as well as of caecal and colonic glands a very strong immunoreactivity to AQP4 was found. Both in the myenteric and submucous ganglia of the large intestine AQP4-positive cells surrounding enteric neurons were observed. We concluded that AQP4 expression in the porcine gastrointestinal tract showed some species-dependent differences in relation to other species. Based on the presented distribution pattern of AQP4, it is likely that the aquaporin plays a role in mucous (but not acid) secretion and intestinal absorptive processes in the pig. Aquaporins, gut, small intestine, large intestine, pig The term aquaporins refers to the group of major intrinsic proteins responsible for highly selective water transport across the cell membrane. The first aquaporin (AQP), formerly known as CHIP28, was discovered by Peter Agre’s group in erythrocytes and proximal tubules of the rat kidney (Denker et al. 1988). But today the family
Transgenic Fish: Researches and Applications

The gene transfer technology applied in commercially important aquatic animals is to enhance the quality or to improve the genetic characters of aquaculture broodstocks. The anti-freezing transgenic salmon and the fast-growing transgenic fish and shellfish have been reported and consider as the most successful cases until now. It highlights a new access to the modification of food fish and shellfish. However, the issues of genetically modified organisms (GMO) are still controversial. Food safety and ecological impacts are the major concerns before GMO are put in the market. For research purpose, zebrafish (Danio rerio) and medaka (Oryzias latipes) have become the most used model organisms since they are primitive vertebrates yet have many advantages over the other. Transgenes is, in vivo transient assay, mutagenesis and knock-down translation of zebrafish embryos are the most effective ways to map expression profiles, to dissect the regulatory cis-elements and to identify the gene functions of vertebral genes. Germ-line transmission is much more easily accessible. Transgenic line carrying a specific tissue tagged by green fluorescent protein (GFP) live marker become a powerful tool to study developmental biology because they enable to recapitulate the expression of endogenous genes. Furthermore, the transparent embryos are available for observation and tracing dynamic expression of a specific gene during embryogenesis. Transgenic fish can also serve as a simple animal model to study human diseases because some zebrafish mutants can faithfully phenocopy human diseases. For application purpose, GFP lines are potentially applied as biosensors for detecting the environmental pollutants. Interestingly, new pet fish species that glows colorfully in the dark can be achieved by transferring fluorescent protein genes. These advantages make the transgenic model fish apt for modern biomedical researches and applications as new materials.
Formulation of Sodium Valproate Nanospanlastics as a Promising Approach for Drug Repurposing in the Treatment of Androgenic Alopecia

Sodium valproate (SV) is an antiepileptic drug that is widely used in the treatment of different seizure disorders. The topical SV has a hair regenerative potential through activating the Wnt/β-catenin pathway and anagen phase induction. The aim of the current investigation was to fabricate nanospanlastics of SV for improving its dermal delivery by providing prolonged drug effect and increasing its permeability for treatment of androgenic alopecia (AGA). SV-loaded nanospanlastics were formulated according to 23 factorial design by ethanol injection method using a non-ionic surfactant (Span 60) and edge activators (EAs), such as Tween 80 and Cremophor RH 40, to explore the influence of different independent variables on entrapment efficiency (EE%) and percentage drug released after 12 h (Q12h) in order to choose the optimized formula using Design-Expert software. The optimized formula (F8) appeared as spherical deformable vesicles with EE% of 90.32 ± 2.18% and Q12h of 90.27 ± 1.98%. F8 exhibited significant improvement of ex vivo permeation than free SV. The clinical study exhibited no comparable difference between F8 and marketed minoxidil lotion. However, F8 demonstrates less adverse effects than minoxidil lotion. Nanospanlastics could be a safe and effective method for improving the topical delivery of SV in the management of AGA.
The New Paradigm of Network Medicine to Analyze Breast Cancer Phenotypes

Breast cancer (BC) is a heterogeneous and complex disease as witnessed by the existence of different subtypes and clinical characteristics that poses significant challenges in disease management. The complexity of this tumor may rely on the highly interconnected nature of the various biological processes as stated by the new paradigm of Network Medicine. We explored The Cancer Genome Atlas (TCGA)-BRCA data set, by applying the network-based algorithm named SWItch Miner, and mapping the findings on the human interactome to capture the molecular interconnections associated with the disease modules. To characterize BC phenotypes, we constructed protein–protein interaction modules based on “hub genes”, called switch genes, both common and specific to the four tumor subtypes. Transcriptomic profiles of patients were stratified according to both clinical (immunohistochemistry) and genetic (PAM50) classifications. 266 and 372 switch genes were identified from immunohistochemistry and PAM50 classifications, respectively. Moreover, the identified switch genes were functionally characterized to select an interconnected pathway of disease genes. By intersecting the common switch genes of the two classifications, we selected a unique signature of 28 disease genes that were BC subtype-independent and classification subtype-independent. Data were validated both in vitro (10 BC cell lines) and ex vivo (66 BC tissues) experiments. Results showed that four of these hub proteins (AURKA, CDC45, ESPL1, and RAD54L) were over-expressed in all tumor subtypes. Moreover, the inhibition of one of the identified switch genes (AURKA) similarly affected all BC subtypes. In conclusion, using a network-based approach, we identified a common BC disease module which might reflect its pathological signature, suggesting a new vision to face with the disease heterogeneity.
A role for the medial temporal lobes in category learning

Despite much research, the role of the medial temporal lobes (MTL) in category learning is unclear. Two unstructured categorization experiments explored conditions that might recruit MTL category learning and memory systems—namely, whether the stimulus display includes one or two stimuli, and whether category membership depends on configural properties of the stimulus features. The results supported three conclusions. First, in agreement with prior research, learning with single stimulus displays depended on striatal-mediated procedural learning. Second, and most important, learning with pair displays was mediated by MTL declarative memory systems. Third, the use of stimuli in which category membership depends on configural properties of the stimulus features made MTL learning slightly more likely. Overall, the results suggested that the MTL are most likely to mediate learning when the participant must decide which of two configural stimuli belongs to a selected category.
Randomized Trial Comparing Preliminary Results of Radialization and Centralization Procedures in Bayne Types 3 and 4 Radial Longitudinal Deficiency.

BACKGROUND The choice of surgical procedure in severe (Bayne and Klug types 3 and 4) radial longitudinal deficiency (RLD) is contentious. Existing studies have reported varying results with both centralization and radialization procedures. The purpose of this study was to compare the clinical and radiologic outcome of radialization and centralization procedures at a short-to-intermediate-term follow-up for the treatment of types 3 and 4 RLD. METHODS Fourteen patients with 17 affected limbs having types 3 or 4 RLD were recruited in this prospective, randomized, controlled trial. After initial application of successive casts for soft tissue distraction, patients were randomized to 2 wrist alignment procedures-centralization and radialization. Clinical and radiologic parameters recorded at stipulated intervals until a final follow-up of 24 months included hand-forearm angle, ulnar bow, forearm length, arm length, total angulation, and range of motion at elbow, wrist, and fingers. RESULTS Centralization was performed in 9 affected limbs, whereas radialization was performed in 8 affected limbs. Nine affected limbs had type 4 RLD, and 8 affected limbs had type 3 RLD. There was no significant difference in the hand-forearm angle in the immediate postoperative period. At 3 months, the radiologic hand-forearm angle increased to 19 degrees in the centralization group, while the radialization group showed an average increase to 4 degrees. This increase in the hand-forearm angle continued at 6-, 12-, and 24-month follow-up assessments. Worsening of the deformity was more in the centralization group, as compared with the radialization group. The forearm length also significantly differed in the 2 groups at 6-, 12-, and 24-month follow-up; however, when adjusted for preoperative lengths, the difference was significant only at 12- and 24-month follow-up. CONCLUSIONS At a short-to-intermediate-term follow-up, radialization fares better than centralization in terms of recurrence of deformity and in terms of affecting the forearm length. Longer follow-up with a larger sample size is needed to draw definitive conclusions. LEVEL OF EVIDENCE Level I.
The Relationship of Diet Quality with Proportion of Daily Energy Contributed by Sandwiches Varies by Age over Adulthood in Racially and Socioeconomically Diverse Adults

Sandwiches are considered a staple in diets of United States adults. Previous research with Healthy Aging in Neighborhoods of Diversity across the Life Span study participants revealed that 16% consume a sandwich dietary pattern providing with 44% of their daily energy. Yet, little is known about the effect of sandwiches on diet quality over time. The study objectives were to determine the relationship of energy contributed by sandwiches to diet quality in this socioeconomically and racially diverse sample categorized by age (<50 years and ≥50 years at baseline) and to describe patterns of sandwich consumption over ~12 years. The analyses included a series of linear mixed-effects regression models, with age as the time variable centered at 50 years. In each model, the main outcome was Healthy Eating Index-2010 score with up to three scores, while the main predictor was % total energy from sandwiches (0, >0–20%, >20%) measured concurrently at each visit. Diet quality of older men with income <125% poverty improved over time for those consuming >0–20% and >20% energy from sandwiches compared to young women with incomes >125% poverty who were non-reporters of sandwiches (β ± SE: 10.93 ± 5.27, p = 0.01; 13.11 ± 4.96, p = 0.01, respectively). The three most common sandwich types reported, in descending order, were cold cuts, beef, and poultry.
Leveraging genetic ancestry to study health disparities

Abstract Research to understand human genomic variation and its implications in health has great potential to contribute in the reduction of health disparities. Biological anthropology can play important roles in genomics and health disparities research using a biocultural approach. This paper argues that racial/ethnic categories should not be used as a surrogate for sociocultural factors or global genomic clusters in biomedical research or clinical settings, because of the high genetic heterogeneity that exists within traditional racial/ethnic groups. Genetic ancestry is used to show variation in ancestral genomic contributions to recently admixed populations in the United States, such as African Americans and Hispanic/Latino Americans. Genetic ancestry estimates are also used to examine the relationship between ancestry‐related biological and sociocultural factors affecting health disparities. To localize areas of genomes that contribute to health disparities, admixture mapping and genome‐wide association studies (GWAS) are often used. Recent GWAS have identified many genetic variants that are highly differentiated among human populations that are associated with disease risk. Some of these are population‐specific variants. Many of these variants may impact disease risk and help explain a portion of the difference in disease burden among racial/ethnic groups. Genetic ancestry is also of particular interest in precision medicine and disparities in drug efficacy and outcomes. By using genetic ancestry, we can learn about potential biological differences that may contribute to the heterogeneity observed across self‐reported racial groups.
Estimating age of spotted and spinner dolphins (Stenella attenuata and Stenella longirostris) from teeth

This paper is an account of preparation and examination techniques and criteria used to estimate age in decalcified and stained tooth thin sections from spinner and spotted dolphins. A dentinal growth layer group (GLG), composed of two thin light and two thicker dark-stained layers, is deposited annually. The GLG component layers are variably visible, but the "ideal" pattern and successive thinning of dentinal GLGs are used as a guide to determine GLG limits. Age-specific thicknesses of dentinal GLGs found in Hawaiian spinner dolphin teeth seem to be applicable to teeth of spotted dolphins and can be used as an aid in locating GLG boundaries. Cementa1 GLGs are composed of a dark-stained and alightly stained layer and usually are deposited at a rate of one per year, but may be deposited every other year or two or three times per year. Two slightly different methods of counting dentinal GLGs are presented, along with guidelines for determining whether dentinal or cementa1 GLG counts provide the best estimate of age for a specimen. (PDF contains 23 pages.)
Prognostic value of vascular endothelial growth factor in both conventional and drug eluting beads transarterial chemoembolization for treatment of unresectable hepatocellular carcinoma in HCV patients

ABSTRACT Objectives This work aimed to measure serum vascular endothelial growth factor (VEGF) levels before and after Conventional transarterial chemoembolization (cTACE) versus drug-eluting beads (DEB)-TACE and evaluate its efficacy in predicting response to therapy and tumor recurrence. Methods 114 patients with unresectable hepatocellular carcinoma complicating hepatitis C virus-related cirrhosis were included. They underwent cTACE (58) or DEB-TACE (56). VEGF serum levels were measured before and on days 1 and 30 after TACE. Patients with complete response (CR) after TACE were followed-up for one year. Statistical analysis was done. Results VEGF level was higher than baseline after cTACE (P < 0.001), and DEB-TACE (P = 0.004). It was also significantly higher in patients with progressive disease (P < 0.001). VEGF level at cut off values of 97.3, 149.8, and 104.1 pg/ml could discriminate disease progression from treatment success with area under ROC curves of 0.806, 0.775, and 0.771, respectively. The sensitivity was 88.9%, 88.9%, and 77.8% and specificity was 62.5%, 64.6 and 66.7%, respectively. However, no relation to tumor recurrence in CR group could be detected after one year. Conclusion VEGF serum levels may predict response to therapy in patients treated by DEB-TACE or cTACE but it has no relation to tumor recurrence.
IOP and Optic Nerve Head Morphology during Scleral Lens Wear

SIGNIFICANCE Scleral lenses (SLs) are increasing in scope, and understanding their ocular health impact is imperative. The unique fit of an SL raises concern that the landing zone causes compression of conjunctival tissue that can lead to resistance of aqueous humor outflow and increased intraocular pressure (IOP). PURPOSE This study aimed to assess changes in optic nerve head morphology as an indirect assessment of IOP and evaluate other IOP assessment methods during SL wear. METHODS Twenty-six healthy adults wore SL on one randomly selected eye for 6 hours, whereas the fellow eye served as a control. Global minimum rim width (optical coherence tomography) and IOP (Icare, Diaton) were measured at baseline, 2 and 6 hours after SL application, and again after SL removal. Central corneal thickness, anterior chamber depth, and fluid reservoir depth were monitored. RESULTS Minimum rim width thinning was observed in the test (−8 μm; 95% confidence interval [CI], −11 to −6 μm) and control (−6 μm; 95% CI, −9 to −3 μm) eyes after 6 hours of SL wear (P < .01), although the magnitude of thinning was not significantly greater in the lens-wearing eyes (P = .09). Mean IOP (Icare) significantly increased +2 mmHg (95% CI, +1 to +3 mmHg) in the test eyes (P = .002), with no change in the control eyes. Mean IOP changes with Diaton were +0.3 mmHg (95% CI, −0.9 to +3.2 mmHg) in the test eyes and +0.4 mmHg (95% CI, −0.8 to +1.7 mmHg) in the control eyes. However, Diaton tonometry showed poor within-subject variation and poor correlation with Icare. No clinically significant changes were observed in central corneal thickness or anterior chamber depth. CONCLUSIONS This study suggests that SLs have a minimal effect on IOP homeostasis in the normal eye during SL wear and an insignificant impact on the optic nerve head morphology in healthy adult eyes.
Remote ischemic conditioning enhances oxygen supply to ischemic brain tissue in a mouse model of stroke: Role of elevated 2,3-biphosphoglycerate in erythrocytes

Oxygen supply for ischemic brain tissue during stroke is critical to neuroprotection. Remote ischemic conditioning (RIC) treatment is effective for stroke. However, it is not known whether RIC can improve brain tissue oxygen supply. In current study, we employed a mouse model of stroke created by middle cerebral artery occlusion (MCAO) to investigate the effect of RIC on oxygen supply to the ischemic brain tissue using a hypoxyprobe system. Erythrocyte oxygen-carrying capacity and tissue oxygen exchange were assessed by measuring oxygenated hemoglobin and oxygen dissociation curve. We found that RIC significantly mitigated hypoxic signals and decreased neural cell death, thereby preserving neurological functions. The tissue oxygen exchange was markedly enhanced, along with the elevated hemoglobin P50 and right-shifted oxygen dissociation curve. Intriguingly, RIC markedly elevated 2,3-biphosphoglycerate (2,3-BPG) levels in erythrocyte, and the erythrocyte 2,3-BPG levels were highly negatively correlated with the hypoxia in the ischemic brain tissue. Further, adoptive transfusion of 2,3-BPG-rich erythrocytes prepared from RIC-treated mice significantly enhanced the oxygen supply to the ischemic tissue in MCAO mouse model. Collectively, RIC protects against ischemic stroke through improving oxygen supply to the ischemic brain tissue where the enhanced tissue oxygen delivery and exchange by RIC-induced 2,3-BPG-rich erythrocytes may play a role.
Male Sterility Caused by Cooling Treatment at the Young Microspore Stage in Rice Plants : XXX. Relation between fertilization and the number of engorged pollen grains among spikelets cooled at different pollen developmental stages

Cooling treatments at different stages of pollen development lowered the percentage of fertilized spikelets through decreasing the number of engorged pollen grains per anther at anthesis. Cooling during the period from anther differentiation to the tetrad phase decreased the number of engorged pollen grains mainly by decreasing the number of differentiated microspores. Cooling in the period from the early microspore phase to the late microspore phase, however, decreased the number of engorged pollen grains primarily by increasing the number of aborted microspores. Cooling at the young microspore stage, which consists of the two phases of the tetrad and the early microspore phase, caused the largest decrease in the number of engorged pollen grains, resulting in the largest decrease in the percentage of fertilization. Cooling at the tetrad phase caused the largest decrease in the number of differentiated microspores, resulting in the largest decrease in the number of engorged pollen grains. On the other hand, cooling at the early microspore phase caused the largest increase in the number of aborted microspores, resulting in the largest decline in the number of engorged pollen grains. These results indicate that the highest susceptibility to coolness of anthers at the young microspore stage, which has been estimated as the percentage of fertilized spikelets, is caused by the high susceptibility to coolness of the differentiation and development of microspores.