Miracle-dz/UniFAR-FTUs huggingface dataset:
Detection of PrPsc in Blood from Sheep Infected with the Scrapie and Bovine Spongiform Encephalopathy Agents

ABSTRACT The role of blood in the iatrogenic transmission of transmissible spongiform encephalopathy (TSE) or prion disease has become an increasing concern since the reports of variant Creutzfeldt-Jakob disease (vCJD) transmission through blood transfusion from humans with subclinical infection. The development of highly sensitive rapid assays to screen for prion infection in blood is of high priority in order to facilitate the prevention of transmission via blood and blood products. In the present study we show that PrPsc, a surrogate marker for TSE infection, can be detected in cells isolated from the blood from naturally and experimentally infected sheep by using a rapid ligand-based immunoassay. In sheep with clinical disease, PrPsc was detected in the blood of 55% of scrapie agent-infected animals (n = 80) and 71% of animals with bovine spongiform encephalopathy (n = 7). PrPsc was also detected several months before the onset of clinical signs in a subset of scrapie agent-infected sheep, followed from 3 months of age to clinical disease. This study confirms that PrPsc is associated with the cellular component of blood and can be detected in preclinical sheep by an immunoassay in the absence of in vitro or in vivo amplification.
Capsaicinoids in the treatment of neuropathic pain: a review

The treatment of neuropathic pain is difficult. Oral pharmaceuticals have significant side effects, and treatment efficacy tends to be modest. The use of topical analgesics reduces the potential for systemic side effects and allows direct application of medications to the area of pain. The natural spicy substance, capsaicin, has historically been known for its topical use. Capsaicin, once applied to the skin, causes a brief initial sensitization followed by a prolonged desensitization of the local pain nerves. This occurs through stimulation of the transient receptor potential vanilloid-1 (TRPV1) expressing pain nerve fibers. While low-dose capsaicin has not resulted in good efficacy, the larger dose 8% topical capsaicin has had some of the best data currently available in the treatment of post-herpetic neuralgia (PHN) and other neuropathic conditions. This paper discusses the data currently existing for capsaicin 8% in the treatment of PHN. It further reviews data for the low-dose capsaicin products and the current status in the development of other capsaicinoids, e.g. resiniferotoxin, and high-concentration liquid capsaicin.
Quantitative Evaluation of Protein Heterogeneity within Herpes Simplex Virus 1 Particles

ABSTRACT Several virulence genes have been identified thus far in the herpes simplex virus 1 genome. It is also generally accepted that protein heterogeneity among virions further impacts viral fitness. However, linking this variability directly with infectivity has been challenging at the individual viral particle level. To address this issue, we resorted to flow cytometry (flow virometry), a powerful approach we recently employed to analyze individual viral particles, to identify which tegument proteins vary and directly address if such variability is biologically relevant. We found that the stoichiometry of the UL37, ICP0, and VP11/12 tegument proteins in virions is more stable than the VP16 and VP22 tegument proteins, which varied significantly among viral particles. Most interestingly, viruses sorted for their high VP16 or VP22 content yielded modest but reproducible increases in infectivity compared to their corresponding counterparts containing low VP16 or VP22 content. These findings were corroborated for VP16 in short interfering RNA experiments but proved intriguingly more complex for VP22. An analysis by quantitative Western blotting revealed substantial alterations of virion composition upon manipulation of individual tegument proteins and suggests that VP22 protein levels acted indirectly on viral fitness. These findings reaffirm the interdependence of the virion components and corroborate that viral fitness is influenced not only by the genome of viruses but also by the stoichiometry of proteins within each virion. IMPORTANCE The ability of viruses to spread in animals has been mapped to several viral genes, but other factors are clearly involved, including virion heterogeneity. To directly probe whether the latter influences viral fitness, we analyzed the protein content of individual herpes simplex virus 1 particles using an innovative flow cytometry approach. The data confirm that some viral proteins are incorporated in more controlled amounts, while others vary substantially. Interestingly, this correlates with the VP16 trans-activating viral protein and indirectly with VP22, a second virion component whose modulation profoundly alters virion composition. This reaffirms that not only the presence but also the amount of specific tegument proteins is an important determinant of viral fitness.
Rift Valley Fever Virus Clearance and Protection from Neurologic Disease Are Dependent on CD4+ T Cell and Virus-Specific Antibody Responses

ABSTRACT Rift Valley fever virus (RVFV) causes outbreaks of severe disease in people and livestock throughout Africa and the Arabian Peninsula. Human RVFV infections generally manifest as a self-limiting febrile illness, but in some individuals, the disease can progress to a fatal encephalitis or hemorrhagic syndrome. Little is known about the host characteristics that predispose development of more severe disease. Early in infection, interferon-mediated antiviral responses are critical for controlling RVFV replication, but the roles of downstream adaptive immune responses in determining clinical outcome have not been examined. Here, using a C57BL/6 mouse disease model, we evaluated the roles of B cells and T cells in RVFV pathogenesis. Given the profound inhibition of the innate response by the viral NSs protein and rapid course of wild-type infection, we utilized an attenuated RVFV lacking NSs to examine host responses following primary infection. Experiments utilizing B-cell-deficient mice or targeted T cell depletions of wild-type mice demonstrated that B cells and CD4+ T cells, but not CD8+ T cells, were critical for mediating viral clearance, even in the presence of a functional innate response. One-third of CD4-depleted mice developed severe neurologic disease following infection, in contrast to virus-infected mock-depleted mice that showed no clinical signs. CD4+ T cells were required for robust IgG and neutralizing antibody responses that correlated with RVFV clearance from peripheral tissues. Furthermore, CD4-depleted mice demonstrated significantly stronger proinflammatory responses relative to controls, suggesting CD4+ T cells regulate immune responses to RVFV infection. Together, these results indicate CD4+ T cells are critical determinants of RVFV pathogenesis and play an important role in preventing onset of neurologic disease.
The diagnosis and management of idiopathic intracranial hypertension and the associated headache

Idiopathic intracranial hypertension (IIH) is a challenging disorder with a rapid increasing incidence due to a close relation to obesity. The onset of symptoms is often insidious and patients may see many different specialists before the IIH diagnosis is settled. A summary of diagnosis, symptoms, headache characteristics and course, as well as existing evidence of treatment strategies is presented and strategies for investigations and management are proposed.
Evolution and Antiviral Specificities of Interferon-Induced Mx Proteins of Bats against Ebola, Influenza, and Other RNA Viruses

ABSTRACT Bats serve as a reservoir for various, often zoonotic viruses, including significant human pathogens such as Ebola and influenza viruses. However, for unknown reasons, viral infections rarely cause clinical symptoms in bats. A tight control of viral replication by the host innate immune defense might contribute to this phenomenon. Transcriptomic studies revealed the presence of the interferon-induced antiviral myxovirus resistance (Mx) proteins in bats, but detailed functional aspects have not been assessed. To provide evidence that bat Mx proteins might act as key factors to control viral replication we cloned Mx1 cDNAs from three bat families, Pteropodidae, Phyllostomidae, and Vespertilionidae. Phylogenetically these bat Mx1 genes cluster closely with their human ortholog MxA. Using transfected cell cultures, minireplicon systems, virus-like particles, and virus infections, we determined the antiviral potential of the bat Mx1 proteins. Bat Mx1 significantly reduced the polymerase activity of viruses circulating in bats, including Ebola and influenza A-like viruses. The related Thogoto virus, however, which is not known to infect bats, was not inhibited by bat Mx1. Further, we provide evidence for positive selection in bat Mx1 genes that might explain species-specific antiviral activities of these proteins. Together, our data suggest a role for Mx1 in controlling these viruses in their bat hosts. IMPORTANCE Bats are a natural reservoir for various viruses that rarely cause clinical symptoms in bats but are dangerous zoonotic pathogens, like Ebola or rabies virus. It has been hypothesized that the interferon system might play a key role in controlling viral replication in bats. We speculate that the interferon-induced Mx proteins might be key antiviral factors of bats and have coevolved with bat-borne viruses. This study evaluated for the first time a large set of bat Mx1 proteins spanning three major bat families for their antiviral potential, including activity against Ebola virus and bat influenza A-like virus, and we describe here their phylogenetic relationship, revealing patterns of positive selection that suggest a coevolution with viral pathogens. By understanding the molecular mechanisms of the innate resistance of bats against viral diseases, we might gain important insights into how to prevent and fight human zoonotic infections caused by bat-borne viruses.
Are There Differing Patterns of Health Care Access and Utilization Among Male Sexual Minorities in the United States?

Disparities in health care access and utilization among male sexual minorities in the United States were explored using data from the National Survey of Family Growth (N = 8,846). Bisexual men had a small disadvantage in health insurance coverage but no differences were found in health insurance or consistency of coverage between gay and heterosexual men. Gay men were more likely to have a usual place of care, but were not more likely to utilize services. The current study provides inconclusive evidence for systematic disparities in health care access and utilization among gay and bisexual men in the United States.
A deficiency of Yang by overuse of Ephedra in traditional medicinal aspects

Ephedra and ephedra alkaloids are sympathomimetic compounds extracted from the genus Ephedra. They have been used to treat colds and provide cough relief for centuries in oriental medicine. Recently, it has been reported that Ephedra plays a crucial role in weight loss and the enhancement of athletic performances. However, the overuse of Ephedra causes cardiovascular side effects such as increases in blood pressure, heart rate, and palpitations. Ephedra’s adverse effects also were mentioned in Shan Han Lun, a famous formulary in traditional Chinese medicine. The present study demonstrated Ephedra’s effects and the deficiency of Yang due to the overuse of Ephedra.
Emerging novel therapies for advanced prostate cancer

This review examines the development and efficacy of novel treatment options for advanced prostate cancer and discusses novel therapies that are on the horizon. Since the introduction of docetaxel as the standard treatment for patients with metastatic castration-resistant prostate cancer (CRPC), a number of different agents have been tested but failed to demonstrate improvement in overall survival (OS). Recently, three novel compounds have demonstrated OS benefit and one other showed reduction in skeletal-related events (SREs). Sipuleucel-T, a novel vaccine, was approved by the US regulatory authorities in April 2010 for patients with early advanced prostate cancer. A new taxane, cabazitaxel, and abiraterone acetate, an androgen biosynthesis inhibitor, have shown an OS benefit in advanced CRPC after docetaxel, leading to drug approval. A new bone-targeting agent, denosumab, a receptor activator of nuclear factor κB ligand (RANKL) antagonist, showed a modest reduction in SREs in comparison to zoledronic acid in patients with bone metastases. Other promising novel agents are currently being tested in the clinical setting of advanced CRPC. These include, androgen receptor inhibitors (MDV3100), androgen biosynthesis inhibitors, angiogenesis inhibitors (thalidomide, lenalidomine, aflibercept, tasquinimod), a novel form of radiotherapy (radium-223), and immune-modulating compounds (PROSTVAC-VF). Improvements in progression-free survival and OS rates, observed with novel agents, in metastatic prostate cancer have led to a shift in treatment paradigm. The challenge will be to position the current established and expected novel treatments in the new landscape of metastatic prostate cancer and to determine at what point and time in the disease course they can best be administered.
Plant Virus Cell-to-Cell Movement Is Not Dependent on the Transmembrane Disposition of Its Movement Protein

ABSTRACT The cell-to-cell transport of plant viruses depends on one or more virus-encoded movement proteins (MPs). Some MPs are integral membrane proteins that interact with the membrane of the endoplasmic reticulum, but a detailed understanding of the interaction between MPs and biological membranes has been lacking. The cell-to-cell movement of the Prunus necrotic ringspot virus (PNRSV) is facilitated by a single MP of the 30K superfamily. Here, using a myriad of biochemical and biophysical approaches, we show that the PNRSV MP contains only one hydrophobic region (HR) that interacts with the membrane interface, as opposed to being a transmembrane protein. We also show that a proline residue located in the middle of the HR constrains the structural conformation of this region at the membrane interface, and its replacement precludes virus movement.
Stabilization of Telomere G-Quadruplexes Interferes with Human Herpesvirus 6A Chromosomal Integration

ABSTRACT Human herpesviruses 6A and 6B (HHV-6A/B) can integrate their genomes into the telomeres of human chromosomes using a mechanism that remains poorly understood. To achieve a better understanding of the HHV-6A/B integration mechanism, we made use of BRACO-19, a compound that stabilizes G-quadruplex secondary structures and prevents telomere elongation by the telomerase complex. First, we analyzed the folding of telomeric sequences into G-quadruplex structures and their binding to BRACO-19 using G-quadruplex-specific antibodies and surface plasmon resonance. Circular dichroism studies indicate that BRACO-19 modifies the conformation and greatly stabilizes the G-quadruplexes formed in G-rich telomeric DNA. Subsequently we assessed the effects of BRACO-19 on the HHV-6A initial phase of infection. Our results indicate that BRACO-19 does not affect entry of HHV-6A DNA into cells. We next investigated if stabilization of G-quadruplexes by BRACO-19 affected HHV-6A's ability to integrate its genome into host chromosomes. Incubation of telomerase-expressing cells with BRACO-19, such as HeLa and MCF-7, caused a significant reduction in the HHV-6A integration frequency (P < 0.002); in contrast, BRACO-19 had no effect on HHV-6 integration frequency in U2OS cells that lack telomerase activity and elongate their telomeres through alternative lengthening mechanisms. Our data suggest that the fluidity of telomeres is important for efficient chromosomal integration of HHV-6A and that interference with telomerase activity negatively affects the generation of cellular clones containing integrated HHV-6A. IMPORTANCE HHV-6A/B can integrate their genomes into the telomeres of infected cells. Telomeres consist of repeated hexanucleotides (TTAGGG) of various lengths (up to several kilobases) and end with a single-stranded 3′ extension. To avoid recognition and induce a DNA damage response, the single-stranded overhang folds back on itself and forms a telomeric loop (T-loop) or adopts a tertiary structure, referred to as a G-quadruplex. In the current study, we have examined the effects of a G-quadruplex binding and stabilizing agent, BRACO-19, on HHV-6A chromosomal integration. By stabilizing G-quadruplex structures, BRACO-19 affects the ability of the telomerase complex to elongate telomeres. Our results indicate that BRACO-19 reduces the number of clones harboring integrated HHV-6A. This study is the first of its kind and suggests that telomerase activity is essential to restore a functional telomere of adequate length following HHV-6A integration.
Prevention of recurrent urinary tract infections by intravesical administration of heparin: a pilot study

Objective: To assess the effect of bladder instillations using heparin on the rate of urinary tract infections in women resistant to standard therapy. Patients and methods: The medical records of all women who received bladder instillations between May 2009 and January of 2010 at the University of Wisconsin urogynecology clinic were reviewed. Eighteen women (mean age 67 years) with a history of recurrent urinary tract infections received intravesical instillations (heparin 40,000 U, 2% lidocaine 8 ml, sodium bicarbonate 4 ml) once weekly for 6 weeks. Patients were considered resistant to standard therapy if their condition failed to respond to chronic suppression antibiotic therapy; they had chronic infections and for this reason could not be placed on chronic suppression; or they were not candidates for chronic suppression due to drug allergies. The number of urinary tract infections was monitored during treatment and for 6 months after therapy. The urinary tract infection rates were compared with the rates of urinary tract infection in the 6 months before treatment. Results: Seventy-eight percent of patients responded to therapy. Subjects were thought to have responded to therapy if there was a greater than 50% reduction in the rate of urinary tract infection. Other variables reviewed included evidence of chronic infection, hormonal status, glomerular filtration rate, age, body mass index, antibiotic allergies, diabetes, hypertension, and chronic antibiotic therapy during bladder instillations. None of these variables were found to be statistically significant. Conclusion: Bladder instillations decreased the rate of urinary tract infection in this pilot study; this effect persisted into the post-treatment period. More research is needed to confirm these preliminary findings.
Development and Pilot Evaluation of a Computer-Based Support System for Women with Breast Cancer

A computer-based support system was developed to help women cope with the crisis of breast cancer. The system, called Comprehensive Health Enhancement Support System (CHESS)contains integrated information, referral, decision, and social support programs. It was developed with intensive input from potential users through needs-assessment surveys and field testing. This article reports on the results of two pilot studies involving 30 women with breast cancer. The preliminary versions of CHESS were used extensively by older and younger women and by college and high school graduates. Participants in the pilot studies suggested several content enhancements and user-friendly aids for the developing system. User surveys indicated that CHESS was easy to use and would be valuable to other women with breast cancer, their partners, and their adult children. The women reported that they experienced more positive emotions and fewer negative emotions as a result of using the system.
Contemporary diagnosis and management of Fournier’s gangrene

Fournier’s gangrene, an obliterative endarteritis of the subcutaneous arteries resulting in gangrene of the overlying skin, is a rare but severe infective necrotizing fasciitis of the external genitalia. Mainly associated with men and those over the age of 50, Fournier’s gangrene has been shown to have a predilection for patients with diabetes as well as people who are long-term alcohol misusers. The nidus for the synergistic polymicrobial infection is usually located in the genitourinary tract, lower gastointestinal tract or skin. Early diagnosis remains imperative as rapid progression of the gangrene can lead to multiorgan failure and death. The diagnosis is often made clinically, although radiography can be helpful when the diagnosis or the extent of the disease is difficult to discern. The Laboratory Risk Indicator for Necrotizing Fasciitis score can be used to stratify patients into low, moderate or high risk and the Fournier’s Gangrene Severity Index (FGSI) can also be used to determine the severity and prognosis of Fournier’s gangrene. Mainstays of treatment include rapid and aggressive surgical debridement of necrotized tissue, hemodynamic support with urgent resuscitation with fluids, and broad-spectrum parental antibiotics. After initial radical debridement, open wounds are generally managed with sterile dressings and negative-pressure wound therapy. In cases of severe perineal involvement, colostomy has been used for fecal diversion or alternatively, the Flexi-Seal Fecal Management System can be utilized to prevent fecal contamination of the wound. After extensive debridement, many patients sustain significant defects of the skin and soft tissue, creating a need for reconstructive surgery for satisfactory functional and cosmetic results.
Experimental Analysis of Mobile-Robot Teleoperation via Shared Impedance Control

In this paper, Internet-based teleoperation of mobile robots for obstacle avoidance is analyzed. A shared impedance-control scheme is presented, and the results of an experimental study for the evaluation of the effects of different teleoperation parameters are reported. In the experimental study, the effects of time delay, operator training, image-display alternatives (virtual model versus real images), viewpoint, and force-reflection method were studied. For this purpose, several hypotheses were formulated and tested through the experiments using the introduced quantitative and qualitative measures. A fuzzy force-reflection controller is also proposed as an alternative force-reflection technique, and its performance is compared with a conventional proportional-derivative-type force-reflection method. The experimental scheme was implemented using MATLAB XPC Target and Simulink. The results could serve as guidelines in the design of teleoperation systems for obstacle avoidance and could also provide directions for further investigations.
The Infectious Molecular Clone and Pseudotyped Virus Models of Human Immunodeficiency Virus Type 1 Exhibit Significant Differences in Virion Composition with Only Moderate Differences in Infectivity and Inhibition Sensitivity

ABSTRACT Two frequently employed methods for generating well-characterized, genetically defined infectious human immunodeficiency virus type 1 in vitro include the use of infectious molecular clones (IMCs) and pseudoviruses (PVs) competent for single-round infection. We compared six matched pairs of IMCs and PVs. The relative amounts of Env incorporated and efficiency of cleavage differed substantially between the two systems. Altering the ratio of proviral genome and env expression plasmids can produce pseudovirions that are structurally more similar to the matched IMCs. Differences in Env incorporation and cleavage translated into moderate differences in assays infectivity and sensitivity to neutralizing antibodies and entry inhibitors.