Miracle-dz/UniFAR-FTUs huggingface dataset:
Dynamic three‐dimensional morphogenesis of intrahepatic bile ducts in mouse liver development

During liver development, biliary epithelial cells differentiated from bipotential hepatic progenitor cells (hepatoblasts) form a cell layer, called the ductal plate surrounding portal veins (PVs), and develop into intrahepatic bile ducts (IBDs) following developmental programs. Because IBDs make duct structures in the liver, it is necessary to perform sequential and three‐dimensional (3D) analyses from the early stages of liver development to address the process of morphogenesis in detail. However, to date, the development of IBDs has mainly been investigated using tissue sections in two‐dimensional planes, and examinations of the 3D morphogenesis and quantitative analyses based on morphometrics have not been performed. Therefore, in this study, we simulated the solid structures of IBDs from mouse embryos to adults in silico, analyzed the subjects for the length and number of developing duct structures, number of predicted connections, and discrete distance from the PV, and examined the developmental process of the IBD in detail in a quantitative manner. Conclusions: Through quantitative analyses with spatiotemporal observations using a 3D structural reconstruction model and morphometrics, we succeeded in constructing a 3D dynamic model of bile duct formation. Because the 3D reconstruction technique used in this study is available for analyzing solid structures in tissues that are difficult to approach, it shows promise for wide use in the fields of biology and medicine. (Hepatology 2015;61:1003–1011)
Correlation of the Resting and Exercise Doppler Ankle/Arm Index to Angiographic Findings

The diagnosis of peripheral vascular occlusive disease has until recently been confirmed only through angiography. However, a noninvasive diagnostic test using Doppler-shift ultrasonography has shown great promise as a method of refining the diagnosis of peripheral vascular occlusive disease. The purpose of this study was to correlate the ankle/arm index (resting versus exercise) to the arteriographic findings and to outline a practical grading system of the se verity of the occlusive disease based on our Doppler index findings. From 500 arterial Doppler studies of 500 patients (1,000 limbs) at the Arizona Heart Insti tute, 93 limbs that had arteriograms and resting and exercising ankle/arm in dices were examined. The resting index was found to be an insensitive index of the severity of the disease. The exercise index did correlate very well with the arteriographic findings: 85% of patients with an excercise index greater than 0.9 were normal or had minimal disease. Most patients with an index of 0.8 to 0.89 had mild disease; 75% of patients with an index of 0.7 to 0.79 had moderate dis ease ; 98% of patients with index of less than 0.69 had severe disease.
Coilin: The first 25 years

Initially identified as a marker of coiled bodies (now Cajal bodies or CBs), the protein coilin was discovered a quarter of century ago. Coilin is now known to scaffold the CB, but its structure and function are poorly understood. Nearly devoid of predicted structural motifs, coilin has numerous reported molecular interactions that must underlie its role in the formation and function of CBs. In this review, we summarize what we have learned in the past 25 years about coilin's structure, post-transcriptional modifications, and interactions with RNA and proteins. We show that genes with homology to human coilin are found in primitive metazoans and comment on differences among model organisms. Coilin's function in Cajal body formation and RNP metabolism will be discussed in the light of these developments.
Assessing a microrNA panel in diagnosing early cholangiocarcinoma

1. Galbraith JW, Franco RA, Donnelly JP, Rodgers JB, Morgan JM, Viles AF, et al. Unrecognized chronic hepatitis C virus infection among baby boomers in the emergency department. HEPATOLOGY 2015;61:776-782. 2. Kazmierczak J, Pawełczyk A, Cortes KC, Radkowski M. Seronegative hepatitis C virus infection. Arch Immunol Ther Exp (Warsz) 2014; 62(2):145-151. 3. Carreno V. Occult hepatitis C virus infection: a new form of hepatitis C. World J Gastroenterol 2006;12(43):6922-6925. 4. Keyvani H, Bokharaei-Salim F, Monavari SH, Esghaei M, Nassiri Toosi M, Fakhim S, et al. Occult hepatitis C virus infection in candidates for liver transplant with cryptogenic cirrhosis. Hepat Mon 2013;13(8): e11290. 5. Castillo I, Bartolom e J, Quiroga JA, Barril G, Carre~ no V. Diagnosis of occult hepatitis C without the need for a liver biopsy. J Med Virol 2010;82(9):1554-1559. 6. Welker MW, Zeuzem S. Occult hepatitis C: how convincing are the current data? HEPATOLOGY 2009;49(2):665-675. 7. Carre~ no V, Bartolom e J, Castillo I, Quiroga JA. New perspectives in occult hepatitis C virus infection. World J Gastroenterol 2012;18(23): 2887-2894. 8. Shazly YE, Hemida K, Rafik M, Swaff RA, Ali-Eldin ZA, GadAllah S. Detection of occult hepatitis C virus among healthy spouses of patients with HCV infection. J Med Virol 2014; doi:10.1002/jmv.24074. 9. Rezaee-Zavareh MS, Einollahi B. Treatment of occult hepatitis C virus infection: does it need special attention? Hepat Mon 2014;14(7): e16665.
FES controlled ambulation with surface electrodes and no orthotics

The subject was a paralyzed T-7 spinal cord injured male. Functional electrical stimulation (FES) was delivered by means of two Respond II units, one attached bilaterally to the quadriceps femoris and the other placed bilaterally on the dorsiflexors of the foot. The electric muscle stimulator settings were set at 30 p.p.s. and 100% output, with a setting intensity of 8. The risetime was 2 s, and there was no falltime. The waveform was biphasic rectangular, and the approximate output was 100 mA. All settings were in the reciprocal mode. Over a period of four months, the subject progressed from walking one step with FES and no orthotics to walking up to 140 ft. <<ETX>>
Regulatory crosstalk between type I and type II toxin-antitoxin systems in the human pathogen Enterococcus faecalis

We discovered a chromosomal locus containing 2 toxin-antitoxin modules (TAs) with an antisense transcriptional organization in the E. faecalis clinical isolate V583. These TAs are homologous to the type I txpA-ratA system and the type II mazEF, respectively. We have shown that the putative MazF is toxic for E. coli and triggers RNA degradation, and its cognate antitoxin MazE counteracts toxicity. The second module, adjacent to mazEF, expresses a toxin predicted to belong to the TxpA type I family found in Firmicutes, and the antisense RNA antidote, RatA. Genomic analysis indicates that the cis-association of mazEF and txpA-ratA modules has been favored during evolution, suggesting a selective advantage for this TA organization in the E. faecalis species. We showed regulatory interplays between the 2 modules, involving transcription control and RNA stability. Remarkably, our data reveal that MazE and MazEF have a dual transcriptional activity: they act as autorepressors and activate ratA transcription, most likely in a direct manner. RatA controls txpA RNA levels through stability. Our data suggest a pivotal role of MazEF in the coordinated expression of mazEF and txpA-ratA modules in V583. To our knowledge, this is the first report describing a crosstalk between type I and II TAs.
Induction of VEGFA mRNA translation by CoCl2 mediated by HuR

Vascular endothelial growth factor (VEGF) A is a master regulator of neovascularization and angiogenesis. VEGFA is potently induced by hypoxia and by pathological conditions including diabetic retinopathy and tumorigenesis. Fine-tuning of VEGFA expression by different stimuli is important for maintaining tissue vascularization and organ homeostasis. Here, we tested the effect of the hypoxia mimetic cobalt chloride (CoCl2) on VEGFA expression in human cervical carcinoma HeLa cells. We found that CoCl2 increased the levels of VEGFA mRNA and VEGFA protein without affecting VEGFA mRNA stability. Biotin pulldown analysis to capture the RNA-binding proteins (RBPs) bound to VEGFA mRNA followed by mass spectrometry analysis revealed that the RBP HuR [human antigen R, a member of the embryonic lethal abnormal vision (ELAV) family of proteins], interacts with VEGFA mRNA. VEGFA mRNA-tagging experiments showed that exposure to CoCl2 increases the interaction of HuR with VEGFA mRNA and promoted the colocalization of HuR and the distal part of the VEGFA 3′-untranslated region (UTR) in the cytoplasm. We propose that under hypoxia-like conditions, HuR enhances VEGFA mRNA translation.
HIV-1 Pr55Gag binds genomic and spliced RNAs with different affinity and stoichiometry

ABSTRACT The HIV-1 Pr55Gag precursor specifically selects genomic RNA (gRNA) from a large variety of cellular and spliced viral RNAs (svRNAs), however the molecular mechanisms of this selective recognition remains poorly understood. To gain better understanding of this process, we analyzed the interactions between Pr55Gag and a large panel of viral RNA (vRNA) fragments encompassing the main packaging signal (Psi) and its flanking regions by fluorescence spectroscopy. We showed that the gRNA harbors a high affinity binding site which is absent from svRNA species, suggesting that this site might be crucial for selecting the HIV-1 genome. Our stoichiometry analysis of protein/RNA complexes revealed that few copies of Pr55Gag specifically associate with the 5′ region of the gRNA. Besides, we found that gRNA dimerization significantly impacts Pr55Gag binding, and we confirmed that the internal loop of stem-loop 1 (SL1) in Psi is crucial for specific interaction with Pr55Gag. Our analysis of gRNA fragments of different length supports the existence of a long-range tertiary interaction involving sequences upstream and downstream of the Psi region. This long-range interaction might promote optimal exposure of SL1 for efficient Pr55Gag recognition. Altogether, our results shed light on the molecular mechanisms allowing the specific selection of gRNA by Pr55Gag among a variety of svRNAs, all harboring SL1 in their first common exon.
Caffeine ameliorates hemodynamic derangements and portosystemic collaterals in cirrhotic rats

Portal hypertension (PH), a pathophysiological derangement of liver cirrhosis, is characterized by hyperdynamic circulation, angiogenesis, and portosystemic collaterals. These may lead to lethal complications, such as variceal bleeding. Caffeine has been noted for its effects on liver inflammation, fibrogenesis, and vasoreactiveness. However, the relevant influences of caffeine in cirrhosis and PH have not been addressed. Spraque‐Dawley rats with common bile duct ligation–induced cirrhosis or sham operation received prophylactic or therapeutic caffeine treatment (50 mg/kg/day, the first or 15th day since operation, respectively) for 28 days. Compared to vehicle (distilled water), caffeine decreased cardiac index, increased systemic vascular resistance, reduced portal pressure (PP), superior mesenteric artery flow, mesenteric vascular density, portosystemic shunting (PSS), intrahepatic angiogenesis, and fibrosis without affecting liver and renal biochemistry. The beneficial effects were reversed by selective adenosine A1 agonist N6‐cyclopentyladenosine (CPA) or A2A agonist GCS21680. Both prophylactic and therapeutic caffeine treatment decreased portal resistance and PP in thioacetamide (200mg/kg, thrice‐weekly for 8 weeks)‐induced cirrhotic rats. Caffeine down‐regulated endothelial nitric oxide synthase, vascular endothelial growth factor (VEGF), phospho‐VEGFR2, and phospho–Akt mesenteric protein expression. Caffeine adversely affected viability of hepatic stellate and sinusoidal endothelial cells, which was reversed by CPA and GCS21680. On the other hand, caffeine did not modify vascular response to vasoconstrictors in splanchnic, hepatic, and collateral vascular beds. Conclusions: Caffeine decreased PP, ameliorated hyperdynamic circulation, PSS, mesenteric angiogenesis, hepatic angiogenesis, and fibrosis in cirrhotic rats. Caffeine may be a feasible candidate to ameliorate PH‐related complications in cirrhosis. (Hepatology 2015;61:1672‐1684)
Groin Pain in Athletes – Clinical Experience

Groin Pain in Athletes – Clinical Experience Dysfunction of lumbo-pelvic area is a common problem in many sports. Due to insufficient data supporting variables predisposing to lumbo-pelvic dysfunction, and a lack of standards in thorough assessment, understanding the overall problem continues to provide clinical complications; and unfortunately, the prognosis is less than promising. Most often this type of non-contact injury in the groin area is seen in dynamic sports involving running, sprinting, and sports performed over longer time periods, where fatigue plays an important role (soccer, rugby, hockey). There have been proposals in identifying most probable factors influencing the occurrence of pelvic overload injury. Among those we can list: muscle strength and balance, training regimen (including warm-up), fatigue, flexibility, body mechanics, sports specific activities, movement technique, previous injury, and psychological state. During clinical assessment by the physician and physiotherapist, many of these risks of injury factors are found. Currently more attention is given to neuromuscular factors that can affect risk of this pathology. Our clinical experience suggests that poor neuromuscular control and lack of strength may significantly contribute to injury in the lumbo-pelvic and groin area. Certain objective indexes (e.g., hamstrings to quadriceps strength H/Q, stability deficits) can be important indicators of injury risk, as well as guidelines for motor dysfunction recovery.
Associação entre HLA e leucemia em uma população brasileira de etnia mista

OBJECTIVE: The main purpose of this study was to investigate the class I HLA antigens and class II HLA allele frequencies in 164 patients with leukemia: 35 patients with ALL (acute lymphoid leukemia), 50 with AML (acute myeloid leukemia) and 78 with CML (chronic myeloid leukemia). METHODS: The genotyping of class I HLA was performed by microlymphocytotoxicity and of class II by PCR-SSP (polymerase chain reaction - sequence specific of primers) (One Lambda, Canoga Park, CA, USA). RESULTS: In patients with LLA, frequencies of HLA-B45 and HLA-B56 were higher (P = 0.02; OR = 3.13; 95%IC = 0.94-10.44; P = 0.03; OR = 3.61; 95%IC = 0.47-27.64, respectively), than in controls. In patients with AML, the frequency of HLA-B7 (P = 0.01; OR = 2.41; 95%IC = 1.25-4.67) was higher than in controls. The presence of HLA-B45 (P= 0.01; OR = 3.29; 95%IC = 1.46-7.40), HLA-DRB1*04 (P = 0.002; OR = 2.17; 95%IC = 1.36-3.46) and HLA-DRB1*08 (P = 0.004; OR = 2.36; 95%IC = 1.34-4.16) was associated to increased risk of CML developing. CONCLUSION: Our results suggest that variants of HLA confer susceptibility to the same forms of leukemia, and could provide new tools for the investigation of genetics and etiology of this disease.
Adaptive remodeling of the biliary architecture underlies liver homeostasis

Serving as the center for metabolism and detoxification, the liver is inherently susceptible to a wide variety of damage imposed by toxins or chemicals. Induction of cell populations with biliary epithelial phenotypes, which include progenitor‐like cells and are referred to as liver progenitor cells, is often observed in histopathological examination of various liver diseases in both human patients and animal models and has been implicated in regeneration. However, the tissue dynamics underlying this phenomenon remains largely unclear. We have developed a simple imaging technique to reveal the global and fine‐scale architecture of the biliary tract spreading in the mouse liver. Using this novel method, we show that the emergence and expansion of liver progenitor cells actually reflect structural transformation of the intrahepatic biliary tree in mouse liver injury models. The biliary branches expanded their area gradually and contiguously along with the course of chronic injury. Relevant regulatory signals known to be involved in liver progenitor cell regulation, including fibroblast growth factor 7 and tumor necrosis factor‐like weak inducer of apoptosis, can modulate the dynamics of the biliary epithelium in different ways. Importantly, the structural transformations of the biliary tree were diverse and corresponded well with the parenchymal injury patterns. That is, when chronic hepatocyte damage was induced in the pericentral area, the biliary branches exhibited an extended structure from the periportal area with apparent tropism toward the distant injured area. Conclusion: The hepatobiliary system possesses a unique and unprecedented structural flexibility and can remodel dynamically and adaptively in response to various injury conditions; this type of tissue plasticity should constitute an essential component to maintain liver homeostasis. (Hepatology 2015;61:2056–2066)
Response to Letters Regarding Article, “Arterial Stiffness and Cardiovascular Events: The Framingham Heart Study”

We thank Dr O'Rourke et al, Drs Safar and Jankowski, and Dr Weber et al for their interest in our recent article.1 Dr O'Rourke et al comment that the “comprehensive battery of measures of aortic stiffness and wave reflection” described in previous communications on this cohort were not mentioned. We reported results for all relevant tonometry data available from the Framingham Heart Study offspring and original cohorts at the noted examination cycles. Although we have assessed additional hemodynamic measures during subsequent examinations in the Framingham offspring and third-generation cohorts, because of insufficient follow-up, we have not yet assessed relations with outcomes for those measures. Dr O'Rourke et al suggest that we dismissed multiple studies that showed wave reflection to be important in predicting outcome. There have been several studies in highly selected patient groups that have shown a relation between augmentation index (AI) and prevalent …
Cost‐effectiveness of hepatitis C treatment for patients in early stages of liver disease

New treatments for hepatitis C virus (HCV) may be highly effective but are associated with substantial costs that may compel clinicians and patients to consider delaying treatment. This study investigated the cost‐effectiveness of these treatments with a focus on patients in early stages of liver disease. We developed a state‐transition (or Markov) model to calculate costs incurred and quality‐adjusted life‐years (QALYs) gained following HCV treatment, and we computed incremental cost‐effectiveness ratios (cost per QALY gained, in 2012 US dollars) for treatment at different stages of liver disease versus delaying treatment until the subsequent liver disease stage. Our analysis did not include the potential treatment benefits associated with reduced non–liver‐related mortality or preventing HCV transmission. All parameter values, particularly treatment cost, were varied in sensitivity analyses. The base case scenario represented a 55‐year‐old patient with genotype 1 HCV infection with a treatment cost of $100,000 and treatment effectiveness of 90%. In this scenario, for a 55‐year‐old patient with moderate liver fibrosis (Metavir stage F2), the cost‐effectiveness of immediately initiating treatment at F2 (versus delaying treatment until F3) was $37,300/QALY. For patients immediately treated at F0 (versus delaying treatment until F1), the threshold of treatment costs that yielded $50,000/QALY and $100,000/QALY cost‐effectiveness ratios were $22,200 and $42,400, respectively. Conclusion: Immediate treatment of HCV‐infected patients with moderate and advanced fibrosis appears to be cost‐effective, and immediate treatment of patients with minimal or no fibrosis can be cost‐effective as well, particularly when lower treatment costs are assumed. (Hepatology 2015;61:1860–1869)
Single Fiber Electromyography

by PAUL L. NUNEZ, 730 pp., ill. , New York, Oxford University Press, 1995. $95.00 This book is an extension of Nunez's earlier work and it further develops his theory of the physical-biologic basic science underlying the electromagnetic activity of the brain. It has two stated aims: to facilitate communications among the many disciplines relevant to EEG and to provide a conceptual framework for the data. The chapters in which Nunez participates directly as an author most strongly adhere to these guiding principles to present a coherent and compelling argument, …
Vardenafil and resveratrol synergistically enhance the nitric oxide/cyclic guanosine monophosphate pathway in corpus cavernosal smooth muscle cells and its therapeutic potential for erectile dysfunction in the streptozotocin-induced diabetic rat: preliminary findings.

INTRODUCTION Phosphodiesterase type 5 (PDE5) inhibitors are very effective agents for erectile dysfunction; however, specific patient populations are hard to treat. The efficacy of PDE5 inhibitors is limited because a minimum amount of nitric oxide (NO) is necessary. Resveratrol, a plant polyphenol, is reported to activate endothelial NO synthase (eNOS) through activation of sirtuin 1. We previously reported that human corpus cavernosal smooth muscle cells (CCSMCs) express eNOS and synthesize cyclic guanosine monophosphate (cGMP) via the NO/cGMP pathway. AIM To investigate the ability of resveratrol and/or vardenafil to increase cGMP in an in vitro model using CCSMCs and to improve erectile function in an in vivo rat model of streptozotocin (STZ)-induced diabetes. METHODS CCSMCs were treated with resveratrol and/or vardenafil. Twenty male Sprague-Dawley rats were randomly divided into five groups (N = 4 in each group): age-matched controls, diabetic controls, and diabetic rats treated with resveratrol, vardenafil, or both in combination for the last 4 weeks of an 8-week period of diabetes induction. MAIN OUTCOME MEASURES Intracellular cGMP measurement, intracovernous pressure (ICP)/mean arterial pressure (MAP) ratio, and smooth muscle/collagen ratio. RESULTS Intracellular cGMP level was elevated by resveratrol treatment in CCSMCs. The combination treatment of resveratrol and vardenafil had a synergistic effect. Diabetic rats showed impairment of erectile function. Treatment with either resveratrol or vardenafil improved ICP/MAP ratio, and combination therapy with resveratrol and vardenafil had a synergistic effect in improvement of ICP/MAP. CONCLUSIONS Treatment with either resveratrol or vardenafil elevated cGMP level in CCSMCs and improved erectile function in STZ-induced diabetic rats. Furthermore, a synergistic effect was observed in vitro and in vivo. Resveratrol or combination therapy of resveratrol and vardenafil can improve erectile function in which NO release is impaired, although further study is needed to confirm the results.