Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of Novel Functions for Hepatitis C Virus Envelope Glycoprotein E1 in Virus Entry and Assembly

ABSTRACT Hepatitis C virus (HCV) envelope glycoprotein complex is composed of E1 and E2 subunits. E2 is the receptor-binding protein as well as the major target of neutralizing antibodies, whereas the functions of E1 remain poorly defined. Here, we took advantage of the recently published structure of the N-terminal region of the E1 ectodomain to interrogate the functions of this glycoprotein by mutating residues within this 79-amino-acid region in the context of an infectious clone. The phenotypes of the mutants were characterized to determine the effects of the mutations on virus entry, replication, and assembly. Furthermore, biochemical approaches were also used to characterize the folding and assembly of E1E2 heterodimers. Thirteen out of 19 mutations led to viral attenuation or inactivation. Interestingly, two attenuated mutants, T213A and I262A, were less dependent on claudin-1 for cellular entry in Huh-7 cells. Instead, these viruses relied on claudin-6, indicating a shift in receptor dependence for these two mutants in the target cell line. An unexpected phenotype was also observed for mutant D263A which was no longer infectious but still showed a good level of core protein secretion. Furthermore, genomic RNA was absent from these noninfectious viral particles, indicating that the D263A mutation leads to the assembly and release of viral particles devoid of genomic RNA. Finally, a change in subcellular colocalization between HCV RNA and E1 was observed for the D263A mutant. This unique observation highlights for the first time cross talk between HCV glycoprotein E1 and the genomic RNA during HCV morphogenesis. IMPORTANCE Hepatitis C virus (HCV) infection is a major public health problem worldwide. It encodes two envelope proteins, E1 and E2, which play a major role in the life cycle of this virus. E2 has been extensively characterized, whereas E1 remains poorly understood. Here, we investigated E1 functions by using site-directed mutagenesis in the context of the viral life cycle. Our results identify unique phenotypes. Unexpectedly, two mutants clearly showed a shift in receptor dependence for cell entry, highlighting a role for E1 in modulating HCV particle interaction with a cellular receptor(s). More importantly, another mutant led to the assembly and release of viral particles devoid of genomic RNA. This unique phenotype was further characterized, and we observed a change in subcellular colocalization between HCV RNA and E1. This unique observation highlights for the first time cross talk between a viral envelope protein and genomic RNA during morphogenesis.
Role of beta-adrenergic receptor blocking agents in hypertensive diseases: personal thoughts as the controversy persists

The long history of the beta-adrenergic receptor blockers for the treatment of hypertension is fraught with many controversies. The first compound had severe untoward effects preventing their use until propranolol was introduced. It was found effective for treatment of angina pectoris since not all patients with hypertension responded to monotherapy with a meaningful reduction of pressure. Nevertheless, the beta-blockers were most effective in: younger patients, especially with hyperkinetic circulation; with co-morbid diseases (e.g. coronary arterial disease with or without prior myocardial infarction); or when used with a diuretic. Subsequently with the advent of meta-analysis to evaluate more generalized experience, controversy resumed with statements made to exclude beta-blockers for initial hypertensive therapy. Support for this argument was gained with reports of patients developing ‘dysglycemia’ with treatment. However, exclusion of any one therapeutic class for a multifactorial disease such as hypertension seems unrealistic. Meta-analysis confounded this conclusion since inadequate numbers of patients having specific clinical and biological characteristics were included (especially young patients). This is particularly important at this time when third-party reimbursement procedures are particularly relevant and when the primary care physician must deal with the individual patient. The NICE report has introduced specific thinking along these lines. In-and-of itself, its recommendations are reasonable, but current articles continue to suggest that the ‘older’ beta-blockers should be excluded from national guidelines for initial antihypertensive therapy. Personally, I disagree; and, no doubt, controversy will continue.
Infecção pelo vírus linfotrópico de células T humanas e transmissão vertical em gestantes de estado da Região Centro-Oeste do Brasil

PURPOSE: to evaluate the prevalence, epidemiological profile (age and origin) and vertical transmission rate of HTLV I/II infection in pregnant women screened by the Pregnant Protection Program of the State of Mato Grosso do Sul Brazil. METHODS: it is a descriptive and transversal study of 32,512 pregnant women submitted to a prenatal screening from November 2002 to October 2003. HTLV I/II infection was diagnosed in all pregnant women by ELISA, confirmed by Western blot and PCR. Congenital HTLV infection was investigated by ELISA test, Western blot and PCR performed on the child's blood sample. The associations between data (age, origin and HTLV infection) were statistically analyzed by the c2 test considering p<0.05 to reject the null hypothesis. RESULTS: a prevalence of 0.1% (37) 0.1% HTLV I/II among 32,512 pregnant women was found. The mean age of the infected women was 25.4 ± 6.4 years, and 78.4% of them were from other areas than the capital. There was no association between maternal age and the patients' origin and infection. In all the eight evaluated newborns, which represented 21.6% of the sample, HTLV I/II serum antibodies were found. Only one newborn infant was breast-fed. CONCLUSIONS : HTLV I/II prevalence among pregnant women of the State of Mato Grosso do Sul Brazil was lower than the rates reported by endemic HTLV countries. This rate was almost the same as that described for non-endemic areas and in some Brazilian reports. The vertical transmission rate of HTLV I/II was 100%, in spite of breast-feeding having been proscribed. Improving the follow-up of the pregnant women and their newborns in the State is mandatory, since only a few infants were investigated.
Wide Variation in the Multiplicity of HIV-1 Infection among Injection Drug Users

ABSTRACT Recent studies indicate that sexual transmission of human immunodeficiency virus type 1 (HIV-1) generally results from productive infection by only one virus, a finding attributable to the mucosal barrier. Surprisingly, a recent study of injection drug users (IDUs) from St. Petersburg, Russia, also found most subjects to be acutely infected by a single virus. Here, we show by single-genome amplification and sequencing in a different IDU cohort that 60% of IDU subjects were infected by more than one virus, including one subject who was acutely infected by at least 16 viruses. Multivariant transmission was more common in IDUs than in heterosexuals (60% versus 19%; odds ratio, 6.14; 95% confidence interval [CI], 1.37 to 31.27; P = 0.008). These findings highlight the diversity in HIV-1 infection risks among different IDU cohorts and the challenges faced by vaccines in protecting against this mode of infection.
Complex Cell Cycle Abnormalities Caused by Human T-Lymphotropic Virus Type 1 Tax

ABSTRACT Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATL), a malignancy of CD4+ T cells whose etiology is thought to be associated with the viral trans-activator Tax. We have shown recently that Tax can drastically upregulate the expression of p27Kip1 and p21CIP1/WAF1 through protein stabilization and mRNA trans-activation and stabilization, respectively. The Tax-induced surge in p21CIP1/WAF1 and p27Kip1 begins in S phase and results in cellular senescence. Importantly, HeLa and SupT1 T cells infected by HTLV-1 also arrest in senescence, thus challenging the notion that HTLV-1 infection causes cell proliferation. Here we use time-lapse microscopy to investigate the effect of Tax on cell cycle progression in two reporter cell lines, HeLa/18x21-EGFP and HeLa-FUCCI, that express enhanced green fluorescent protein (EGFP) under the control of 18 copies of the Tax-responsive 21-bp repeat element and fluorescent ubiquitin cell cycle indicators, respectively. Tax-expressing HeLa cells exhibit elongated or stalled cell cycle phases. Many of them bypass mitosis and become single senescent cells as evidenced by the expression of senescence-associated β-galactosidase. Such cells have twice the normal equivalent of cellular contents and hence are enlarged, with exaggerated nuclei. Interestingly, nocodazole treatment revealed a small variant population of HeLa/18x21-EGFP cells that could progress into mitosis normally with high levels of Tax expression, suggesting that genetic or epigenetic changes that prevent Tax-induced senescence can occur spontaneously at a detectable frequency.
Hemodynamic and hormonal patterns of untreated essential hypertension in men and women

Background: Knowledge of hemodynamic factors accounting for the development of hypertension should help to tailor therapeutic approaches and improve blood pressure control. Few data exist regarding sex differences of hemodynamic factors contributing to hypertension progression among patients with untreated nondiabetic stage I and II prehypertension (PreHyp) as defined by the Joint National Committee-7 guidelines (JNC-7). Methods: We utilized noninvasive impedance cardiography, applanation tonometry and plasma measures of angiotensin II, angiotensin (1–7), serum aldosterone, high-sensitivity C-reactive protein (hs-CRP) and cytokine biomarkers of inflammation to characterize the hemodynamic and hormonal profile of 100 patients with untreated hypertension (39 women). Results: Despite there being no differences between women and men in terms of office blood pressure, heart rate and body mass index, men demonstrated lower values of pulse pressure, systemic vascular resistance, brachial artery pulse wave velocity and augmentation index. In each of the three hypertension categories, the increased blood pressure in men was associated with significant augmentations in stroke volume and cardiac output compared with women. Sex-related hemodynamic differences were associated in women with higher plasma levels of leptin, hs-CRP, plasma angiotensin II and serum aldosterone, and no differences in the serum concentrations of cytokinins. In women but not men, hs-CRP correlated with plasma concentrations of transforming growth factor β1 (TGFβ1) and body weight; in addition, plasma TGFβ1 correlated with levels of serum vascular cell adhesion molecule 1. Conclusion: The impact of sex differences in the hemodynamic factors accounting for the elevation in arterial pressure in subjects with essential hypertension has been poorly characterized or this information is not available. We suggest that this gap in knowledge may adversely influence choices of drug treatment since our study shows for the first time significant differences in the hemodynamic and hormonal mechanisms accounting for the increased blood pressure in women compared to men.
Residues within the C-Terminal Arm of the Herpes Simplex Virus 1 Glycoprotein B Ectodomain Contribute to Its Refolding during the Fusion Step of Virus Entry

ABSTRACT Herpesvirus entry into cells requires coordinated interactions among several viral glycoproteins. The final membrane fusion step of entry is executed by glycoprotein B (gB), a class III viral fusion protein that is conserved across all herpesviruses. Fusion proteins are metastable proteins that mediate fusion by inserting into a target membrane and refolding from a prefusion to postfusion conformation to bring the viral and cell membranes together. Although the structure of gB has been solved in a conformation that likely represents its postfusion form, its prefusion structure and the details of how it refolds to execute fusion are unknown. The postfusion gB structure contains a trimeric coiled-coil at its core and a long C-terminal arm within the ectodomain packs against this coil in an antiparallel manner. This coil-arm complex is reminiscent of the six-helix bundle that provides the energy for fusion in class I fusogens. To determine the role of the coil-arm complex, we individually mutated residues in the herpes simplex virus 1 gB coil-arm complex to alanine and assessed the contribution of each residue to cell-cell and virus-cell fusion. Several coil mutations resulted in a loss of cell surface expression, indicating that the coil residues are important for proper processing of gB. Three mutations in the arm region (I671A, H681A, and F683A) reduced fusion without affecting expression. Combining these three arm mutations drastically reduced the ability of gB to execute fusion; however, fusion function could be restored by adding known hyperfusogenic mutations to the arm mutant. We propose that the formation of the coil-arm complex drives the gB transition to a postfusion conformation and the coil-arm complex performs a function similar to that of the six-helix bundle in class I fusion. Furthermore, we suggest that these specific mutations in the arm may energetically favor the prefusion state of gB.
Influenza Virus M2 Ion Channel Protein Is Necessary for Filamentous Virion Formation

ABSTRACT Influenza A virus buds from cells as spherical (∼100-nm diameter) and filamentous (∼100 nm × 2 to 20 μm) virions. Previous work has determined that the matrix protein (M1) confers the ability of the virus to form filaments; however, additional work has suggested that the influenza virus M2 integral membrane protein also plays a role in viral filament formation. In examining the role of the M2 protein in filament formation, we observed that the cytoplasmic tail of M2 contains several sites that are essential for filament formation. Additionally, whereas M2 is a nonraft protein, expression of other viral proteins in the context of influenza virus infection leads to the colocalization of M2 with sites of virus budding and lipid raft domains. We found that an amphipathic helix located within the M2 cytoplasmic tail is able to bind cholesterol, and we speculate that M2 cholesterol binding is essential for both filament formation and the stability of existing viral filaments.
Taurine supplementation has anti-atherogenic and anti-inflammatory effects before and after incremental exercise in heart failure

Background: The purpose of this study was to examine the anti-atherogenic and anti-inflammatory effect of supplemental taurine prior to and following incremental exercise in patients with heart failure (HF). Methods: Patients with HF and left ventricle ejection fraction less than 50%, and placed in functional class II or III according to the New York Heart Association classification, were randomly assigned to two groups: (1) taurine supplementation; or (2) placebo. The taurine group received oral taurine (500 mg) 3 times a day for 2 weeks, and performed exercise before and after the supplementation period. The placebo group followed the same protocol, but with a starch supplement (500 mg) rather than taurine. The incremental multilevel treadmill test was done using a modified Bruce protocol. Results: Our results indicate that inflammatory indices [C-reactive protein (CRP), platelets] decreased in the taurine group in pre-exercise, post-supplementation and post-exercise, post-supplementation as compared with pre-exercise, pre-supplementation (p < 0.05) whereas these indices increased in pre-exercise, post-supplementation and post-exercise, post-supplementation as compared with pre-exercise, pre-supplementation in the placebo group (p < 0.05). Our results also show that atherogenic indices [Castelli’s Risk Index-I (CRI-I), Castelli’s Risk Index-II (CRI-II) and Atherogenic Coefﬁcient (AC)] decreased in the taurine group in pre-exercise, post-supplementation and post-exercise, post-supplementation as compared with pre-exercise, pre-supplementation (p < 0.05). No such changes were noted in the placebo group (p > 0.05). Conclusions: our results suggest that 2 weeks of oral taurine supplementation increases the taurine levels and has anti-atherogenic and anti-inflammatory effects prior to and following incremental exercise in HF patients.
Rift Valley Fever Virus MP-12 Vaccine Is Fully Attenuated by a Combination of Partial Attenuations in the S, M, and L Segments

ABSTRACT Rift Valley fever (RVF) is a mosquito-borne zoonotic disease endemic to Africa and characterized by a high rate of abortion in ruminants and hemorrhagic fever, encephalitis, or blindness in humans. RVF is caused by Rift Valley fever virus (RVFV; family Bunyaviridae, genus Phlebovirus), which has a tripartite negative-stranded RNA genome (consisting of the S, M, and L segments). Further spread of RVF into countries where the disease is not endemic may affect the economy and public health, and vaccination is an effective approach to prevent the spread of RVFV. A live-attenuated MP-12 vaccine is one of the best-characterized RVF vaccines for safety and efficacy and is currently conditionally licensed for use for veterinary purposes in the United States. Meanwhile, as of 2015, no other RVF vaccine has been conditionally or fully licensed for use in the United States. The MP-12 strain is derived from wild-type pathogenic strain ZH548, and its genome encodes 23 mutations in the three genome segments. However, the mechanism of MP-12 attenuation remains unknown. We characterized the attenuation of wild-type pathogenic strain ZH501 carrying a mutation(s) of the MP-12 S, M, or L segment in a mouse model. Our results indicated that MP-12 is attenuated by the mutations in the S, M, and L segments, while the mutations in the M and L segments confer stronger attenuation than those in the S segment. We identified a combination of 3 amino acid changes, Y259H (Gn), R1182G (Gc), and R1029K (L), that was sufficient to attenuate ZH501. However, strain MP-12 with reversion mutations at those 3 sites was still highly attenuated. Our results indicate that MP-12 attenuation is supported by a combination of multiple partial attenuation mutations and a single reversion mutation is less likely to cause a reversion to virulence of the MP-12 vaccine. IMPORTANCE Rift Valley fever (RVF) is a mosquito-transmitted viral disease that is endemic to Africa and that has the potential to spread into other countries. Vaccination is considered an effective way to prevent the disease, and the only available veterinary RVF vaccine in the United States is a live-attenuated MP-12 vaccine, which is conditionally licensed. Strain MP-12 is different from its parental pathogenic RVFV strain, strain ZH548, because of the presence of 23 mutations. This study determined the role of individual mutations in the attenuation of the MP-12 strain. We found that full attenuation of MP-12 occurs by a combination of multiple mutations. Our findings indicate that a single reversion mutation will less likely cause a major reversion to virulence of the MP-12 vaccine.
Robust Neural Control for Dynamic Positioning Ships With the Optimum-Seeking Guidance

This paper deals with the optimum dynamic positioning control problem for marine ships in the presence of actuator gain uncertainties and unknown environmental disturbances. The proposed approach is formulated as two modules, i.e., the guidance part and the control part. By utilizing the improved extremum seeking algorithm, the optimum-seeking guidance is developed in this note to generate the reasonable heading guidance for dynamic positioning ships. The main purpose of this design is to ensure the closed-loop system running efficiently and environment-friendly in practice. Combined with the proposed guidance principle, a robust neural control algorithm is developed based on the dynamic surface control, neural networks, and the robust neural damping technique. In this algorithm, the strong couplings of state variables and the gain uncertainty of actuators are tackled, and the system uncertainties are compensated requiring less (or no) information of the hydrodynamic structure, the actuator model and the external disturbances. Considerable effort is made to guarantee the semiglobal uniform ultimate bounded stability by employing the Lyapunov theory. The advantages of the proposed control scheme could be summarized as two points. First, the control approach is with the properties of optimization and energy-saving, which is meaningful for applying the theoretical algorithm. Second, the pitch ratio of thrusters is selected as the control inputs of interest, which is measurable in the practical plant. These characteristics would facilitate the implementation of the algorithm in engineering. Two examples are provided to verify the performance of the proposed scheme.
Cleavage of Influenza Virus Hemagglutinin by Airway Proteases TMPRSS2 and HAT Differs in Subcellular Localization and Susceptibility to Protease Inhibitors

ABSTRACT Proteolytic cleavage of the influenza virus surface glycoprotein hemagglutinin (HA) by host cell proteases is crucial for infectivity and virus spread. The proteases HAT (human airway trypsin-like protease) and TMPRSS2 (transmembrane protease serine S1 member 2) known to be present in the human airways were previously identified as proteases that cleave HA. We studied subcellular localization of HA cleavage and cleavage inhibition of seasonal influenza virus A/Memphis/14/96 (H1N1) and pandemic virus A/Hamburg/5/2009 (H1N1) in MDCK cells that express HAT and TMPRSS2 under doxycycline-induced transcriptional activation. We made the following observations: (i) HA is cleaved by membrane-bound TMPRSS2 and HAT and not by soluble forms released into the supernatant; (ii) HAT cleaves newly synthesized HA before or during the release of progeny virions and HA of incoming viruses prior to endocytosis at the cell surface, whereas TMPRSS2 cleaves newly synthesized HA within the cell and is not able to support the proteolytic activation of HA of incoming virions; and (iii) cleavage activation of HA and virus spread in TMPRSS2- and HAT-expressing cells can be suppressed by peptide mimetic protease inhibitors. The further development of these inhibitors could lead to new drugs for influenza treatment.