Miracle-dz/UniFAR-FTUs huggingface dataset:
Cellular and molecular mechanisms of fungal β-(1→6)-glucan in macrophages

Over the last 40 yr, the majority of research on glucans has focused on β-(1→3)-glucans. Recent studies indicate that β-(1→6)-glucans may be even more potent immune modulators than β-(1→3)-glucans. Mechanisms by which β-(1→6)-glucans are recognized and modulate immunity are unknown. In this study, we examined the interaction of purified water-soluble β-(1→6)-glucans with macrophage cell lines and primary peritoneal macrophages and the cellular and molecular consequences of this interaction. Our results indicate the existence of a specific β-(1→6)-glucan receptor that internalizes the glucan ligand via a clathrin-dependent mechanism. We show that the known β-(1→3)-glucans receptors are not responsible for β-(1→6)-glucan recognition and interaction. The receptor–ligand uptake/interaction has an apparent dissociation constant (KD) of ∼4 µM, and was associated with phosphorylation of ERK and JNK but not IκB-α or p38. Our results indicate that macrophage interaction with β-(1→6)-glucans may lead to modulation of genes associated with anti-fungal immunity and recruitment/activation of neutrophils. In summary, we show that macrophages specifically bind and internalize β-(1→6)-glucans followed by activation of intracellular signaling and modulation of anti-fungal immune response-related gene regulation. Thus, we conclude that the interaction between innate immunity and β-(1→6)-glucans may play an important role in shaping the anti-fungal immune response.
A Model System for Overcoming Physical Work Barriers

A model system is proposed to help understand the relationship between personal and work factors that affect participation in work. The proposed model includes a hierarchical open-ended format for considering worker and job properties with special emphasis on musculoskeletal disorders. The first level of the analysis is based on information that can be obtained from interviewing patients, workers, supervisors and health care providers, and provides broad categories of information that can be used to anticipate barriers to working and to plan further studies to evaluate and overcome barriers. The sequence and depth of subsequent analysis depends on the circumstances, e.g., finding a new job, returning to work following an injury, or a new job design. If the worker is undergoing medical treatment, the treating health care provider usually has final authority for the return to work decisions, although the decisions can be greatly influenced by job information provided. Two cases are presented to illustrate development and application of the model.
Diagnostic Accuracy of Serum 1,3-β-d-Glucan for Pneumocystis jiroveci Pneumonia, Invasive Candidiasis, and Invasive Aspergillosis: Systematic Review and Meta-Analysis

ABSTRACT Serum 1,3-β-d-glucan (BG) assay may be helpful as a marker for the diagnosis of Pneumocystis jiroveci pneumonia (PJP) and invasive fungal infection (IFI). We conducted a systematic review to assess the diagnostic accuracy of this assay. We searched MEDLINE, Web of Science, Cochrane Collaboration databases, Ichushi-Web, reference lists of retrieved studies, and review articles. Our search included studies of serum BG assay that used (i) positive cytological or direct microscopic examination of sputum or bronchoalveolar lavage fluid for PJP and (ii) European Organization for Research and Treatment of Cancer or similar criteria for IFI as a reference standard and provided data to calculate sensitivity and specificity. Only major fungal infections such as invasive candidiasis and invasive aspergillosis were included in the IFI group. Twelve studies for PJP and 31 studies for IFI were included from January 1966 to November 2010. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic curve (AUC-SROC) for PJP were 96% (95% confidence interval [95% CI], 92% to 98%), 84% (95% CI, 83% to 86%), 102.3 (95% CI, 59.2 to 176.6) and 0.96 (95% CI, 0.94 to 0.99), respectively. No heterogeneity was found. For IFI, the values were 80% (95% CI, 77% to 82%), 82% (95% CI, 81% to 83%), 25.7 (95% CI, 15.0 to 44.1), and 0.88 (95% CI, 0.82 to 0.93). Heterogeneity was significant. The diagnostic accuracy of the BG assay is high for PJP and moderate for IFI. Because the sensitivity for PJP is particularly high, the BG assay can be used as a screening tool for PJP.
Differences in Methicillin-Resistant Staphylococcus aureus Strains Isolated from Pediatric and Adult Patients from Hospitals in a Large County in California

ABSTRACT Studies of U.S. epidemics of community- and health care-associated methicillin-resistant Staphylococcus aureus (MRSA) suggested differences in MRSA strains in adults and those in children. Comprehensive population-based studies exploring these differences are lacking. We conducted a prospective cohort study of inpatients in Orange County, CA, collecting clinical MRSA isolates from 30 of 31 Orange County hospitals, to characterize differences in MRSA strains isolated from children compared to those isolated from adults. All isolates were characterized by spa typing. We collected 1,124 MRSA isolates from adults and 159 from children. Annual Orange County population estimates of MRSA inpatient clinical cultures were 119/100,000 adults and 22/100,000 children. spa types t008, t242, and t002 accounted for 83% of all isolates. The distribution of these three spa types among adults was significantly different from that among children (χ2 = 52.29; P < 0.001). Forty-one percent of adult isolates were of t008 (USA300), compared to 69% of pediatric isolates. In multivariate analyses, specimens from pediatric patients, wounds, non-intensive care unit (ICU) wards, and hospitals with a high proportion of Medicaid-insured patients were significantly associated with the detection of t008 strains. While community- and health care-associated MRSA reservoirs have begun to merge, significant differences remain in pediatric and adult patient populations. Community-associated MRSA spa type t008 is significantly more common in pediatric patients.
Clinical Validation of the cobas 4800 HPV Test for Cervical Screening Purposes

ABSTRACT This study shows that the clinical performance and reproducibility of the cobas 4800 HPV test for high-risk human papillomavirus (HPV) detection fulfill the criteria as formulated in international guidelines of HPV test requirements for cervical screening purposes. Accordingly, the cobas 4800 HPV test can be considered clinically validated for cervical screening.
Rapid Identification of Mycobacteria and Drug-Resistant Mycobacterium tuberculosis by Use of a Single Multiplex PCR and DNA Sequencing

ABSTRACT Tuberculosis (TB) remains a significant global health problem for which rapid diagnosis is critical to both treatment and control. This report describes a multiplex PCR method, the Mycobacterial IDentification and Drug Resistance Screen (MID-DRS) assay, which allows identification of members of the Mycobacterium tuberculosis complex (MTBC) and the simultaneous amplification of targets for sequencing-based drug resistance screening of rifampin-resistant (rifampinr), isoniazidr, and pyrazinamider TB. Additionally, the same multiplex reaction amplifies a specific 16S rRNA gene target for rapid identification of M. avium complex (MAC) and a region of the heat shock protein 65 gene (hsp65) for further DNA sequencing-based confirmation or identification of other mycobacterial species. Comparison of preliminary results generated with MID-DRS versus culture-based methods for a total of 188 bacterial isolates demonstrated MID-DRS sensitivity and specificity as 100% and 96.8% for MTBC identification; 100% and 98.3% for MAC identification; 97.4% and 98.7% for rifampinr TB identification; 60.6% and 100% for isoniazidr TB identification; and 75.0% and 98.1% for pyrazinamider TB identification. The performance of the MID-DRS was also tested on acid-fast-bacterium (AFB)-positive clinical specimens, resulting in sensitivity and specificity of 100% and 78.6% for detection of MTBC and 100% and 97.8% for detection of MAC. In conclusion, use of the MID-DRS reduces the time necessary for initial identification and drug resistance screening of TB specimens to as little as 2 days. Since all targets needed for completing the assay are included in a single PCR amplification step, assay costs, preparation time, and risks due to user errors are also reduced.
Evaluation of New Biomarker Genes for Differentiating Haemophilus influenzae from Haemophilus haemolyticus

ABSTRACT PCR detecting the protein D (hpd) and fuculose kinase (fucK) genes showed high sensitivity and specificity for identifying Haemophilus influenzae and differentiating it from H. haemolyticus. Phylogenetic analysis using the 16S rRNA gene demonstrated two distinct groups for H. influenzae and H. haemolyticus.
Concurrent Serotyping and Genotyping of Pneumococci by Use of PCR and Electrospray Ionization Mass Spectrometry

ABSTRACT A pneumococcal serotyping/genotyping system (PSGS) was developed based upon targeted PCR, followed by electrospray ionization mass spectrometry and amplicon base composition analysis. Eight multiplex PCRs, 32 targeting serotype-determining capsular biosynthetic loci, and 8 targeting multilocus sequence typing (MLST) loci were employed for each of 229 highly diverse Streptococcus pneumoniae isolates. The most powerful aspect of the PSGS system was the identification of capsular serotypes accounting for the majority of invasive and carried pneumococcal strains. Altogether, 45 different serotypes or serogroups were correctly predicted among the 196 resolvable isolates, with only 2 unexpected negative results. All 33 isolates that represented 23 serotypes not included in the PSGS yielded negative serotyping results. A genotyping database was constructed using the base compositions of 65- to 100-bp sections of MLST alleles compiled within http://www.mlst. net. From this database, one or more MLST sequence types (STs) that comprised a PSGS genotype were identified. The end result of more PSGS genotypes (163) than conventional STs actually tested (155) was primarily due to amplification failures of 1 to 3 targets. In many instances, the PSGS genotype could provide resolution of single- and double-locus variants. This molecular serotyping/genotyping scheme is well suited to rapid characterization of large sets of pneumococcal isolates.
Inhaled corticosteroids and the increased risk of pneumonia: what’s new? A 2015 updated review

There is a considerable amount of evidence that supports the possibility of an increased risk of pneumonia associated with prolonged use of inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD). However, as yet, no statistically significant increase in pneumonia-related 30-day mortality in patients on ICS has been demonstrated. The lack of objective pneumonia definitions and radiological confirmations have been a major source of bias, because of the similarities in clinical presentation between pneumonia and acute exacerbations of COPD. One of the newer fluticasone furoate studies overcomes these limitations and also provides an assessment of a range of doses, suggesting that the therapeutic window is quite narrow and that conventional dosing has probably been too high, although the absolute risk may be different compared to other drugs. Newer studies were not able to rule out budesonide as responsible for pneumonia, as previous evidence suggested, and there is still need for evidence from head-to-head comparisons in order to better assess possible intra-class differences. Although the exact mechanisms by which ICS increase the risk of pneumonia are not fully understood, the immunosuppressive effects of ICS on the respiratory epithelium and the disruption of the lung microbiome are most likely to be implicated. Given that COPD represents such a complex and heterogeneous disease, attempts are being made to identify clinical phenotypes with clear therapeutic implications, in order to optimize the pharmacological treatment of COPD and avoid the indiscriminate use of ICS. If deemed necessary, gradual withdrawal of ICS appears to be well tolerated. Vaccination against pneumococcus and influenza should be emphasized in patients with COPD receiving ICS. Physicians should keep in mind that signs and symptoms of pneumonia in COPD patients may be initially indistinguishable from those of an exacerbation, and that patients with COPD appear to be at increased risk of developing pneumonia as a complication of ICS therapy.
Cytokines IL-1 β , IL-6, and TNF- α EnhanceIn Vitro Growth of Bacteria

We have previously reported that in acute respiratory distress syndrome (ARDS), nonsurvivors have persistent elevation in pulmonary and circulating proinflammatory cytokine levels over time and a high rate of nosocomial infections antemortem. In these patients, none of the proven or suspected nosocomial infections caused a transient or sustained increase in plasma proinflammatory cytokine levels above preinfection values. We hypothesized that cytokines secreted by the host during ARDS may favor the growth of bacteria. We conducted an in vitro study of the growth of three bacteria clinically relevant in nosocomial infections, evaluating their in vitro response to various concentrations of tumor necrosis factor (TNF)- α , interleukin (IL)-1 β , and IL-6. We found that all three bacterial species showed concentration-dependent growth enhancement when incubated with one or more tested cytokines and that blockade by specific neutralizing cytokine MoAb significantly inhibited cytokine-induced growth. When compa.
Coexistence of Multiple Genotypes, Including Newly Identified Genotypes, in Outbreaks of Gastroenteritis Due to Norovirus in Japan

ABSTRACT Norovirus (NV) (formerly called Norwalk-like virus) is the most common cause of acute nonbacterial gastroenteritis in humans. Recently, we reported an NV genotyping scheme based on variability in the capsid N-terminal/shell (N/S) domain gene (Katayama et al., Virology 299:225-239, 2002). We found 19 genotypes, including nine of genogroup I and 10 of genogroup II. In the present study, we investigated the molecular epidemiology of NV from 66 outbreaks that occurred in Saitama Prefecture, Japan, from 1997 to 2002. We screened 416 stool specimens by a real-time reverse transcription (RT)-PCR method (Kageyama et al., J. Clin. Microbiol. 41:1548-1557, 2003) and detected 156 NV-positive specimens, from which we amplified the capsid N/S domain gene by RT-PCR and then cloned the PCR products. After sequencing these clones, we obtained 368 sequence variants (strains). By applying our classification scheme to the strains from Saitama and other published strains, we identified a total of 31 genotypes, including an additional five genotypes for genogroup I and seven for genogroup II. Of the 31 genotypes, 26 were present in the Saitama area during that time period. These results provide additional evidence for the great diversity of human NV genotypes. Specimens from all shellfish-related infections contained multiple genotypes, including several new genotypes. On the other hand, single genotypes were observed mostly in outbreaks that originated in semiclosed communities. Thus, the number of NV genotypes in each outbreak depended on the route of transmission.
Gammaherpesvirus 68 Infection of Endothelial Cells Requires both Host Autophagy Genes and Viral Oncogenes for Optimal Survival and Persistence

ABSTRACT Gammaherpesvirus-associated neoplasms include tumors of lymphocytes, epithelial cells, and endothelial cells (ECs). We previously showed that, unlike most cell types, ECs survive productive gammaherpesvirus 68 (γHV68) infection and achieve anchorage-independent growth, providing a cellular reservoir for viral persistence. Here, we demonstrated autophagy in infected ECs by analysis of LC3 localization and protein modification and that infected ECs progress through the autophagosome pathway by LC3 dual fluorescence and p62 analysis. We demonstrate that pharmacologic autophagy induction results in increased survival of infected ECs and, conversely, that autophagy inhibition results in death of infected EC survivors. Furthermore, we identified two viral oncogenes, v-cyclin and v-Bcl2, that are critical to EC survival and that modify EC proliferation and survival during infection-induced autophagy. We found that these viral oncogenes can also facilitate survival of substrate detachment in the absence of viral infection. Autophagy affords cells the opportunity to recover from stressful conditions, and consistent with this, the altered phenotype of surviving infected ECs was reversible. Finally, we demonstrated that knockdown of critical autophagy genes completely abrogated EC survival. This study reveals a viral mechanism which usurps the autophagic machinery to promote viral persistence within nonadherent ECs, with the potential for recovery of infected ECs at a distant site upon disruption of virus replication.
Extensive Mutagenesis of the Conserved Box E Motif in Duck Hepatitis B Virus P Protein Reveals Multiple Functions in Replication and a Common Structure with the Primer Grip in HIV-1 Reverse Transcriptase

ABSTRACT Hepadnaviruses, including the pathogenic hepatitis B virus (HBV), replicate their small DNA genomes through protein-primed reverse transcription, mediated by the terminal protein (TP) domain in their P proteins and an RNA stem-loop, ϵ, on the pregenomic RNA (pgRNA). No direct structural data are available for P proteins, but their reverse transcriptase (RT) domains contain motifs that are conserved in all RTs (box A to box G), implying a similar architecture; however, experimental support for this notion is limited. Exploiting assays available for duck HBV (DHBV) but not the HBV P protein, we assessed the functional consequences of numerous mutations in box E, which forms the DNA primer grip in human immunodeficiency virus type 1 (HIV-1) RT. This substructure coordinates primer 3′-end positioning and RT subdomain movements during the polymerization cycle and is a prime target for nonnucleosidic RT inhibitors (NNRTIs) of HIV-1 RT. Box E was indeed critical for DHBV replication, with the mutations affecting the folding, ϵ RNA interactions, and polymerase activity of the P protein in a position- and amino acid side chain-dependent fashion similar to that of HIV-1 RT. Structural similarity to HIV-1 RT was underlined by molecular modeling and was confirmed by the replication activity of chimeric P proteins carrying box E, or even box C to box E, from HIV-1 RT. Hence, box E in the DHBV P protein and likely the HBV P protein forms a primer grip-like structure that may provide a new target for anti-HBV NNRTIs.
Selection of Arteriolipidosis-Prone Rats (ALR)

Arteriolipidosis-prone rats (ALR) were successfully selected among SHR by repeatedly breeding rats with a greater reactive hypercholesterolemia. When fed on a HFC diet for few weeks, they rapidly developed hypercholesterolemia and ring-like fat deposits in mesenteric and cerebrobasal arteries. The establishment of ALR has proven that not only hypertension but also possible genetic abnormality in cholesterol metabolism is important for atherogenesis.
Interplay between Ovine Bone Marrow Stromal Cell Antigen 2/Tetherin and Endogenous Retroviruses

ABSTRACT Endogenous betaretroviruses (enJSRVs) of sheep are expressed abundantly in the female reproductive tract and play a crucial role in conceptus development and placental morphogenesis. Interestingly, the colonization of the sheep genome by enJSRVs is likely still ongoing. During early pregnancy, enJSRV expression correlates with the production of tau interferon (IFNT), a type I IFN, by the developing conceptus. IFNT is the pregnancy recognition signal in ruminants and possesses potent antiviral activity. In this study, we show that IFNT induces the expression of bone marrow stromal cell antigen 2 (BST2) (also termed CD317/tetherin) both in vitro and in vivo. The BST2 gene is duplicated in ruminants. Transfection assays found that ovine BST2 proteins (oBST2A and oBST2B) block release of viral particles produced by intact enJSRV loci and of related exogenous and pathogenic jaagsiekte sheep retrovirus (JSRV). Ovine BST2A appears to restrict enJSRVs more efficiently than oBST2B. In vivo, the expression of BST2A/B and enJSRVs in the endometrium increases after day 12 and remains high between days 14 and 20 of pregnancy. In situ hybridization analyses found that oBST2A is expressed mainly in the endometrial stromal cells but not in the luminal and glandular epithelial cells, in which enJSRVs are highly expressed. In conclusion, enJSRVs may have coevolved in the presence of oBST2A/B by being expressed in different cellular compartments of the same organ. Viral expression in cells unable to express BST2 may be one of the mechanisms used by retroviruses to escape restriction.
An Anti-Inflammatory Role of VEGFR2/Src Kinase Inhibitor in Herpes Simplex Virus 1-Induced Immunopathology

ABSTRACT Corneal neovascularization represents a key step in the blinding inflammatory stromal keratitis (SK) lesion caused by ocular infection with herpes simplex virus (HSV). In this report, we describe a novel approach for limiting the angiogenesis caused by HSV infection of the mouse eye. We show that topical or systemic administration of the Src kinase inhibitor (TG100572) that inhibits downstream molecules involved in the vascular endothelial growth factor (VEGF) signaling pathway resulted in markedly diminished levels of HSV-induced angiogenesis and significantly reduced the severity of SK lesions. Multiple mechanisms were involved in the inhibitory effects. These included blockade of IL-8/CXCL1 involved in inflammatory cells recruitment that are a source of VEGF, diminished cellular infiltration in the cornea, and reduced proliferation and migration of CD4+ T cells into the corneas. As multiple angiogenic factors (VEGF and basic fibroblast growth factor [bFGF]) play a role in promoting angiogenesis during SK and since Src kinases are involved in signaling by many of them, the use of Src kinase inhibition represents a promising way of limiting the severity of SK lesions the most common cause of infectious blindness in the Western world.
Review: Stroke prevention: modifying risk factors

Risk factor modification remains as the principal aspect of care for stroke prevention. Understanding of risk factors has advanced and several options are now available to treat modifiable risk factors. However, effective treatment remains a challenging task in clinical practice. Prevention begins with awareness of risk factors by patients and clinicians. Risk factor assessment along with overall stroke risk estimation should be part of evaluation of patients with stroke, and used with careful clinical judgment. In this review, we discuss the impact of modifiable traditional vascular risk factors on ischemic stroke, interventions for stroke prevention, and evidence for early treatment of risk factors where available, as well as areas of research progress. Emphasis should be put on the education of patients, the community, and medical personnel. Future research in the field of genetic determinants of vascular risk factors and stroke will increase our understanding of the underlying mechanisms of cerebrovascular disease and likely result in development of new therapies and individualized programs for stroke prevention.