Miracle-dz/UniFAR-FTUs huggingface dataset:
Cytomegalovirus (CMV) DNA Load Is an Independent Predictor of CMV Disease and Survival in Advanced AIDS

ABSTRACT The impact of cytomegalovirus (CMV) on human immunodeficiency virus type 1 (HIV-1) disease progression has been controversial. In this study, we sought to determine if CMV viral load is independent of HIV-1 viral load in predicting CMV disease and survival. Our findings indicate that in patients with advanced AIDS, CMV DNA load is an independent marker of CMV disease and survival and is more predictive than HIV-1 RNA load. Moreover, patients who respond to preemptive therapy with oral ganciclovir, with resulting undetectable levels of CMV DNA, in their plasma, have a significantly lower risk of developing CMV disease and higher rates of survival, despite stable or increasing HIV-1 RNA loads. These data provide support for CMV as an independent risk factor for mortality in persons with advanced AIDS and further suggest that effective preemptive therapy for CMV can improve patient survival rates.
Vitronectin in bacterial pathogenesis: a host protein used in complement escape and cellular invasion

The multifunctional human glycoprotein vitronectin (Vn) plays a significant role in cell migration, tissue repair and regulation of membrane attack complex (MAC) formation. It also promotes neutrophil infiltration and, thus, enhances the inflammatory process during infection. In the host, a balanced homeostasis is maintained by Vn due to neutralization of the self‐reactivity of the MAC. On the other hand, Vn bound to the bacterial surface protects from MAC‐mediated lysis and enhances adhesion. Gram‐negative bacterial pathogens including Moraxella catarrhalis, Haemophilus influenzae and Neisseria gonorrhoeae use Vn recruitment to prevent MAC deposition at their surface. Moreover, Gram‐positive bacterial pathogens such as Streptococcus pneumoniae and S. pyogenes utilize Vn for effective adhesion to host cells and subsequent internalization. Vitronectin has an Arg–Gly–Asp (RGD) sequence for binding the host cell integrin receptors and a separate bacterial‐binding domain for pathogens, and thus more likely functions to cross‐link bacteria and epithelial cells. Once bacteria are attached to the vitronectin–integrin complex, various host cell‐signalling events are activated and promote internalization. In this review, we focus on the important roles of vitronectin in bacterial pathogenesis and describe different strategies used by pathogens to evade the host response by the help of this intriguing molecule.
The impact of visual impairment and eye disease on vision-related quality of life in a Mexican-American population: proyecto VER.

PURPOSE To describe the relationship of visual acuity impairment and eye disease on vision-related quality of life, as measured by the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), in a cross-sectional, population-based study of older Hispanic persons living in Arizona. METHODS A random sample of block groups with Hispanic residents in Nogales and Tucson, Arizona, were selected for study. Participants were interviewed at home with a questionnaire that included the NEI-VFQ-25, an instrument measuring vision-related quality of life. Acuity was obtained with Early Treatment Diabetic Retinopathy Study (ETDRS) charts and standard protocol. Cataract was determined by clinical examination, diabetic retinopathy was diagnosed on stereo fundus photographs, and glaucoma was diagnosed on the basis of clinical examination and visual field results. Analyses were done to determine the degree of association between subscale scores and acuity in the better-seeing eye, monocular visual impairment, and specific eye diseases, with adjustment for acuity. RESULTS Of the 4774 participants in the study, 99.7% had completed questionnaires that were not completed by proxy. Participants with visual impairment had associated decrements in scores on all subscales, with a decrease in presenting acuity associated with a worse score (P < 0.05), after adjustment for demographic variables. Monocular impairment was also associated with lower scores in several subscales. In those with cataract, low acuity explained most of the low scores, but those with glaucoma or diabetic retinopathy had low scores independent of acuity. CONCLUSIONS In this study of Mexican-American persons aged 40 or more, monocular impairment and better-eye acuity was associated with a decrease in most domains representing quality of life. Subjects with uncorrected refractive error, cataract, diabetic retinopathy, and glaucoma had associated decrements in quality of life, many not explained by loss of acuity. Further work on the specific measures of vision associated with reported decreases in quality of life, such as visual field or contrast sensitivity, is warranted.
Poxvirus-Based Active Immunotherapy with PD-1 and LAG-3 Dual Immune Checkpoint Inhibition Overcomes Compensatory Immune Regulation, Yielding Complete Tumor Regression in Mice

Poxvirus-based active immunotherapies mediate anti-tumor efficacy by triggering broad and durable Th1 dominated T cell responses against the tumor. While monotherapy significantly delays tumor growth, it often does not lead to complete tumor regression. It was hypothesized that the induced robust infiltration of IFNγ-producing T cells into the tumor could provoke an adaptive immune evasive response by the tumor through the upregulation of PD-L1 expression. In therapeutic CT26-HER-2 tumor models, MVA-BN-HER2 poxvirus immunotherapy resulted in significant tumor growth delay accompanied by a robust, tumor-infiltrating T cell response that was characterized by low to mid-levels of PD-1 expression on T cells. As hypothesized, this response was countered by significantly increased PD-L1 expression on the tumor and, unexpectedly, also on infiltrating T cells. Synergistic benefit of anti-tumor therapy was observed when MVA-BN-HER2 immunotherapy was combined with PD-1 immune checkpoint blockade. Interestingly, PD-1 blockade stimulated a second immune checkpoint molecule, LAG-3, to be expressed on T cells. Combining MVA-BN-HER2 immunotherapy with dual PD-1 plus LAG-3 blockade resulted in comprehensive tumor regression in all mice treated with the triple combination therapy. Subsequent rejection of tumors lacking the HER-2 antigen by treatment-responsive mice without further therapy six months after the original challenge demonstrated long lasting memory and suggested that effective T cell immunity to novel, non-targeted tumor antigens (antigen spread) had occurred. These data support the clinical investigation of this triple therapy regimen, especially in cancer patients harboring PD-L1neg/low tumors unlikely to benefit from immune checkpoint blockade alone.
Quantum Confinement Effects in Extremely Thin Body Germanium n-MOSFETs

We explore the impact of varying channel thickness (from 8 to 1.5 nm) on extremely thin germanium n-MOSFETs, by explicitly incorporating the quantum confinement effects in the band structure calculations using the first principle density functional theory. In Ge (001) thin films in the sub-10-nm regime, the X valley becomes the lowest conduction band valley and is mostly responsible for the charge transport as in silicon. Considering device parameters as per the international technology roadmap for semiconductors (ITRS) projected device specifications for the year 2024, we use the confinement-modulated effective mass to calculate the drain current employing the fully ballistic nonequilibrium Green's function transport model. The best suited thickness for digital applications is found to be 1.5 nm with subthreshold slope of 83.8 mV/decade, ION/IOFF of 1.8 × 104, and an ION exceeding ITRS targets.
A novel exhaustive search algorithm for predicting the conformation of polypeptide segments in proteins

We present a fast ab initio method for the prediction of local conformations in proteins. The program, PETRA, selects polypeptide fragments from a computer‐generated database (APD) encoding all possible peptide fragments up to twelve amino acids long. Each fragment is defined by a representative set of eight ϕ/ψ pairs, obtained iteratively from a trial set by calculating how fragments generated from them represent the protein databank (PDB). Ninety‐six percent (96%) of length five fragments in crystal structures, with a resolution better than 1.5 Å and less than 25% identity, have a conformer in the database with less than 1 Å root‐mean‐square deviation (rmsd). In order to select segments from APD, PETRA uses a set of simple rule‐based filters, thus reducing the number of potential conformations to a manageable total. This reduced set is scored and sorted using rmsd fit to the anchor regions and a knowledge‐based energy function dependent on the sequence to be modelled. The best scoring fragments can then be optimized by minimization of contact potentials and rmsd fit to the core model. The quality of the prediction made by PETRA is evaluated by calculating both the differences in rmsd and backbone torsion angles between the final model and the native fragment. The average rmsd ranges from 1.4 Å for three residue loops to 3.9 Å for eight residue loops. Proteins 2000;40:135–144. © 2000 Wiley‐Liss, Inc.
Spillover Effects of Internal Control Weakness Disclosures: The Role of Audit Committees and Board Connections

We find that firms are less likely to report an internal control material weakness (as mandated by the Sarbanes-Oxley Act) in a given year if one of their audit committee members is concurrently on the board of a firm that disclosed a material weakness within the prior three years. We find a similar spillover effect for financial restatement disclosures. The spillover from material weakness disclosures is evident only if a shared director has more experience with the disclosing firm or can channel more information about the disclosed material weakness. Our findings suggest that prior director experiences outside the firm influence the work of audit committees inside the firm. One rationale is that a director’s prior experience with an adverse disclosure helps diffuse important insights and serves as a catalyst for improvements in a firm’s internal control and financial reporting practices. An alternative explanation, which we cannot dismiss, holds that a director’s prior experience helps a firm to under-report material weaknesses and financial restatements without any attendant improvements in the underlying practices.
Atg1 allows second-signaled autophagic cell death in Dictyostelium

We investigated the role of Atg1 in autophagic cell death (ACD) in a Dictyostelium monolayer model. The model is especially propitious, not only because of genetic tractability and absence of apoptosis machinery, but also because induction of ACD requires two successive exogenous signals, first the combination of starvation and cAMP, second the differentiation factor DIF-1. This enables one to analyze separately first-signal-induced autophagy and subsequent second-signal-induced ACD. We used mutants of atg1, a gene that plays an essential role in the initiation of autophagy. Upon starvation/cAMP, in contrast to parental cells, atg1 mutant cells showed irreversible lesions, clearly establishing a protective role for Atg1. Upon subsequent exposure to DIF-1 or to more ACD-specific second signals, starved parental cells progressed to ACD, but starved atg1 mutant cells did not, showing that Atg1 was required for ACD. Thus, in the same cells Atg1 was required in two apparently opposite ways, upon first-signaling for cell survival and upon second-signaling for ACD. Our findings strongly suggest that Atg1, thus presumably autophagy, protects the cells from starvation-induced cell death, allowing subsequent induction of ACD by the second signal. ACD is therefore not only “with” autophagy (since it showed signs of autophagy throughout), but is also “allowed by” autophagy. This does not exclude a role for autophagy also after second signaling. These results may account for discrepancies reported in the literature, encourage searches for second signals in different developmental models of ACD, and incite caution in autophagy-related therapeutic attempts.
Molecular characterization of Chlamydia trachomatis and Chlamydia psittaci plasmids

Plasmids from Chlamydia trachomatis LGV-434 (serotype L2) and Chlamydia psittaci meningopneumonitis strain Cal-10 were cloned into the BamHI and EcoRI sites of pBR322, respectively. The recombinant plasmids pCTL2 and pCPMn, each containing an entire respective chlamydial plasmid, were transformed into Escherichia coli. The sizes of the plasmids of C. trachomatis and C. psittaci were 7.3 and 6.2 kilobases, respectively. The two plasmids were found to be distinct by restriction endonuclease analysis, DNA-DNA hybridization, and electron microscopic heteroduplex analysis. However, partial homology was observed between restriction fragments of pCTL2 and pCPMn by Southern blot analysis. Polypeptide products encoded by these plasmids were synthesized in vitro by an E. coli-directed transcription-translation system and in vivo in E. coli maxicells and minicells. None of these polypeptides was immunoreactive with anti-chlamydial sera by immunoblotting or immunoprecipitation. Based on the comparative analysis data, the C. trachomatis and C. psittaci plasmids were found to share little genetic relatedness.
The path to approval of new drugs for diabetes

Introduction: The evaluation of agents to treat elevated blood glucose is straightforward and is accomplished with short duration studies, but it is more difficult to demonstrate safety of these agents over long periods of clinical use. Numerous large studies have raised questions as to the cardiovascular risks of certain drugs such as the thiazolidinediones and even challenged the wisdom of aggressive attempts to normalize plasma glucose. As a result of this uncertainty, the FDA issued new Guidance to Industry to assess cardiovascular risk. This new approach has markedly increased the burden to achieve approval of new diabetes drugs. Areas covered: The author has reviewed the recent history of drug approvals for diabetes drugs, using MEDLINE searches and freedom of information requests to the FDA. The thiazolidinedione saga illustrates that certain risks do not clearly manifest in the relatively short duration studies needed to evaluate control of blood sugar levels. Furthermore, the UKPDS and DCCT-EDIC studies show us that the lowering of plasma glucose has a beneficial effect which can only be reliably assessed over a very long time period. Expert opinion: The present day approval process is flawed in the conception that regulatory agencies can guarantee absolute safety. It is important to acknowledge that the risk–benefit relationship for new agents can only be determined by ongoing long-term clinical experience and prolonged longitudinal controlled studies. The increased costs of thorough safety evaluations must be defrayed by early initial approval and marketing of new therapeutic agents. Patent lifetimes and marketing exclusivity should be prolonged until results of long-term studies are finalized.
Cellular localization of mitochondria contributes to Kv channel-mediated regulation of cellular excitability in pulmonary but not mesenteric circulation

Mitochondria are proposed to be a major oxygen sensor in hypoxic pulmonary vasoconstriction (HPV), a unique response of the pulmonary circulation to low oxygen tension. Mitochondrial factors including reactive oxygen species, cytochrome c, ATP, and magnesium are potent modulators of voltage-gated K+ (Kv) channels in the plasmalemmal membrane of pulmonary arterial (PA) smooth muscle cells (PASMCs). Mitochondria have also been found close to the plasmalemmal membrane in rabbit main PA smooth muscle sections. Therefore, we hypothesized that differences in mitochondria localization in rat PASMCs and systemic mesenteric arterial smooth muscle cells (MASMCs) may contribute to the divergent oxygen sensitivity in the two different circulations. Cellular localization of mitochondria was compared with immunofluorescent labeling, and differences in functional coupling between mitochondria and Kv channels was evaluated with the patch-clamp technique and specific mitochondrial inhibitors antimycin A (acting at complex III of the mitochondrial electron transport chain) and oligomycin A (which inhibits the ATP synthase). It was found that mitochondria were located significantly closer to the plasmalemmal membrane in PASMCs compared with MASMCs. Consistent with these findings, the effects of the mitochondrial inhibitors on Kv current (IKv) were significantly more potent in PASMCs than in MASMCs. The cytoskeletal disruptor cytochalasin B (10 μM) also altered mitochondrial distribution in PASMCs and significantly attenuated the effect of antimycin A on the voltage-dependent parameters of IKv. These findings suggest a greater structural and functional coupling between mitochondria and Kv channels specifically in PASMCs, which could contribute to the regulation of PA excitability in HPV.
Exposure of Oat Seedlings to Blue Light Results in Amplified Phosphorylation of the Putative Photoreceptor for Phototropism and in Higher Sensitivity of the Plants to Phototropic Stimulation

Dark recovery of blue light-induced in vitro phosphorylation in oat (Avena sativa L.) seedlings after in vivo preirradiation with blue light revealed different recovery kinetics for the coleoptile base and tip. Although, in both cases, maximum in vitro phosphorylation was observed 90 min after in vivo blue light treatment, the phosphorylation levels for the entire base were about 3-fold higher than those found in nonpreirradiated plants. The tip response only slightly exceeded that of the dark controls. The fluence applied during preirradiation determined the extent of the increase in phosphorylation. Consequently, unilateral irradiation and subsequent dark incubation resulted in a more pronounced increase in phosphorylation in the irradiated than in the shaded side of the coleoptile base. Furthermore, blue light-irradiation conditions, known to induce neither first- nor second-positive curvature in nonpreirradiated plants, stimulated both asymmetric distribution of protein phosphorylation and second-positive phototropic curvature in the coleoptile base when administered to blue light-pretreated plants. Based on these data, we conclude that photosensitivity of the coleoptile base increases upon exposure to blue light in a time-and fluence-dependent manner, providing an excellent explanation of the invalidity of the Bunsen-Roscoe reciprocity law for second-positive phototropism.
Expression of dihydropyrimidine dehydrogenase, thymidylate synthase, p53 and p21 in metastatic liver tumor from colorectal cancer after 5-fluorouracil-based chemotherapy.

BACKGROUND The expression of genes thought to be related to 5-FU chemosensitivity has been extensively investigated. However, little data is available on the expression patterns of these genes after chemotherapy. PATIENTS AND METHODS We investigated the expression of four genes, DPD, TS, p53 and p21, in the metastatic liver lesions obtained from colorectal cancer patients who had been treated with hepatic arterial infusions of 5-fluorouracil(5-FU)-based chemotherapy. RESULTS Expression of DPD, TS and p53 in the metastatic liver lesions was significantly higher in the chemotherapy-response group than in the no response group. In the response group, viable cancer cell nests were seen in confined spaces surrounded by fibrous tissue. It was of interest that these cancer cells in the response group showed conspicuous immunoreactivity of DPD, TS and p53. CONCLUSION An analysis of genes involved in 5-FU sensitivity revealed that surviving tumor cells exhibited resistance characteristics, indicating that the chemotherapy regimen should be altered, even in partially responding cases, unless the response is pathologically complete.
Evaluation of Iloprost to Prevent Vasospasm in Coronary Artery Bypass Grafts

This study assessed the efficacy of iloprost in relieving vasospasm in coronary artery bypass grafts. Radial artery (RA), left internal thoracic artery (LITA) and saphenous vein (SV) grafts were taken from 20 patients (13 men and seven women, mean age 63.8 years [range 48 − 74 years]) scheduled to undergo coronary artery bypass grafting. Ten 3 mm vascular rings were cut from each graft and kept under tension for at least 60 min. They were kept alive with 37°C oxygenated Krebs solution. Smooth muscle contraction was achieved with phenylephrine before iloprost was administered every 2 min, starting at a concentration of 10−9 mol/l and increasing in logarithmic increments to a concentration of 10−5 mol/l. The vasodilation response to iloprost started in all samples at a concentration of 10−9 mol/l and increased with each incremental increase in iloprost concentration up to 10−5 mol/l. These data suggest that local administration of iloprost has a role in relieving graft vasospasm during harvesting and preparation for coronary artery bypass grafting.
Ensuring More Sustainable Reporting in Europe Using Non-Financial Disclosure—De Facto and De Jure Evidence

Non-financial disclosure has become increasingly popular, as it can satisfy the information needs of a growing range of stakeholders. Because traditional financial reports cannot provide comprehensive accountability, several frameworks and guidelines for facilitating non-financial information disclosure have been developed. Recently, the European Union issued Directive 2014/95/EU (EU Directive) and subsequent guidelines (EU Guidelines 2017/C215/01 [EUG]) to mandate European entities of public interest to convey non-financial information to improve such organizations’ accountability toward their stakeholders. This paper studies the European stage of non-financial reporting from a regulatory and practical point of view. To this end, the first research objective is to analyze the elements that the EUG have in common with the IIRF and the GRI 4 guidelines. Second, the paper proposes a first analysis to assess the compliance to the EUG by performing a content analysis on a sample of annual reports and integrated reports (IR) drafted by the 50 biggest European companies. The results highlight that the content elements required by the Directive exceed the requirements of the two frameworks and that there is already a high level of compliance by European big companies with the EUG. More specifically, particular attention is devoted to Social, Employee and Environmental Matter s. Accordingly, the companies demonstrated a common awareness of the necessity to provide an exhaustive amount of social and environmental disclosure in order to maintain legitimacy. Also the disclosure on Principal Risks and Their Management is widespread to meet investors’ and stakeholders’ requirements in recent years with respect to the general level of risk disclosure provided by companies.