Assessing quality of life in pulmonary arterial hypertension: An independent prognostic marker.

Pulmonary arterial hypertension (PAH, or PH Group 1), a disease of aberrant pulmonary vascular remodeling, causing progressive right heart failure (RHF) due to elevation of pulmonary vascular resistance (PVR). Patient mortality risk stratification guides choice and intensity of pharmacological intervention and is assessed by haemodynamics (especially PVR) as well as noninvasive tools including WHO functional class (FC), 6-min walk distance (6MWD), and NT-proBNP levels. Quality of life (QOL) assessment is acknowledged as a central aspect of patient-centered care, but our study sought to extend QOL's role as an additional noninvasive risk marker that could further refine risk stratification and hence therapeutic choices within a "treatment to target" paradigm (aiming to achieve low-risk status). This study found that QOL assessment using the PAH-SYMPACT© physical activity tool provided enhanced, independent mortality risk information, with one unit rise in this score associated with a 41% increase in likelihood risk (odds ratio 1.41, 95% confidence interval: 1.01-1.98 (p < 0.05)) of falling within intermediate versus low-group category. We therefore found further support for additional prognostic value being conferred by measurement of QOL as part of routine PAH evaluation, reinforcing its critical role.

Biologically significant interaction of human herpesvirus 8 viral interferon regulatory factor 4 with ubiquitin-specific protease 7.

Human herpesvirus 8 (HHV-8), associated with Kaposi sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman disease, encodes four interferon regulatory factor homologs, vIRFs 1-4, that interact with and inhibit various mediators of host-cell defense against virus infection. A cellular protein targeted by all the vIRFs is ubiquitin-specific protease 7 (USP7); while replication-modulatory and latently infected PEL-cell pro-viability phenotypes of USP7 targeting have been identified for vIRFs 1-3, the significance of the interaction of vIRF-4 with USP7 has remained undetermined. Here we show, through genetic ablation of the vIRF-4-USP7 interaction in infected cells, that vIRF-4 association with USP7 is necessary for optimal expression of vIRF-4 and normal HHV-8 replication. Findings from experiments on transfected and infected cells identified ubiquitination of vIRF-4 via K48-linkage and USP7-binding-associated suppression of vIRF-4 ubiquitination and, in infected cells, increased vIRF-4 expression. Analysis of IFN-I induction and associated signaling as a function of vIRF-4 and its interaction with USP7 identified a role of each in innate-immune suppression. Finally, activation via K63-polyubiquitination of the innate-immune signaling mediator TRAF3 was found to be suppressed by vIRF-4 in a USP7-binding-associated manner in infected cells, but not in transfected cells, likely via binding-regulated expression of vIRF-4. Together, our data identify the first examples of vIRF ubiquitination and a vIRF substrate of USP7, enhanced expression of vIRF-4 via its interaction with USP7, and TRAF3-inhibitory activity of vIRF-4. The findings address, for the first time, the biological significance of the interaction of vIRF-4 with USP7 and reveal a mechanism of vIRF-4-mediated innate-immune evasion and pro-replication activity via TRAF3 regulation. IMPORTANCE: HHV-8 homologs of cellular interferon regulatory factors (IRFs), involved in host-cell defense against virus infection, interact in an inhibitory fashion with IRFs and other mediators of antiviral innate immunity. These interactions are of demonstrated or hypothesized importance for successful primary, productive (lytic), and latent (persistent) infection by HHV-8. While HHV-8 vIRF-4 is known to interact physically with USP7 deubiquitinase, a key regulator of various cellular proteins, the functional and biological significance of the interaction has not been addressed. The present study identifies the interaction as important for HHV-8 productive replication and, indeed, for vIRF-4 expression and reveals a new function of vIRF-4 via inhibition of the activity of TRAF3, a pivotal mediator of host-cell antiviral activity through activation of cellular IRFs and induction of type-I interferons. These findings identify potential targets for the development of novel anti-HHV-8 agents, such as those able to disrupt vIRF-4-USP7 interaction or vIRF-4-stabilizing USP7 activity.

Association between socioeconomic deprivation and bone health status in the UK biobank cohort participants.

The effect of deprivation on total bone health status has not been well defined. We examined the relationship between socioeconomic deprivation and poor bone health and falls and we found a significant association. The finding could be beneficial for current public health strategies to minimise disparities in bone health. PURPOSE: Socioeconomic deprivation is associated with many illnesses including increased fracture incidence in older people. However, the effect of deprivation on total bone health status has not been well defined. To examine the relationship between socioeconomic deprivation and poor bone health and falls, we conducted a cross-sectional study using baseline measures from the United Kingdom (UK) Biobank cohort comprising 502,682 participants aged 40-69 years at recruitment during 2006-2010. METHOD: We examined four outcomes: 1) low bone mineral density/osteopenia, 2) fall in last year, 3) fracture in the last five years, and 4) fracture from a simple fall in the last five years. To measure socioeconomic deprivation, we used the Townsend index of the participant's residential postcode. RESULTS: At baseline, 29% of participants had low bone density (T-score of heel < -1 standard deviation), 20% reported a fall in the previous year, and 10% reported a fracture in the previous five years. Among participants experiencing a fracture, 60% reported the cause as a simple fall. In the multivariable logistic regression model after controlling for other covariates, the odds of a fall, fracture in the last five years, fractures from simple fall, and osteopenia were respectively 1.46 times (95% confidence interval [CI] 1.42-1.49), 1.26 times (95% CI 1.22-1.30), 1.31 times (95% CI 1.26-1.36) and 1.16 times (95% CI 1.13-1.19) higher for the most deprived compared with the least deprived quantile. CONCLUSION: Socioeconomic deprivation was significantly associated with poor bone health and falls. This research could be beneficial to minimise social disparities in bone health.

Interactive effects of climate-atmospheric cycling on aquatic communities and ecosystem shifts in mountain lakes of southeastern Tibetan Plateau.

Recent climate warming and atmospheric reactive nitrogen (Nr) deposition are affecting a broad spectrum of physical, ecological and human systems that may be irreversible on a century time scale and have the potential to cause regime shifts in ecological systems. These changes may alter the limnological conditions with important but still unclear effects on lake ecosystems. We present changes in cladoceran with comparisons to diatom assemblages over the past ~200 years from high-resolution, well-dated sediment cores retrieved from six high mountain lakes in the southeastern (SE) margin of the Tibetan Plateau. Our findings suggest that warming and the exponential increase of atmospheric Nr deposition are the major drivers of ecological regime changes. Shifts in cladoceran and diatom communities in high alpine lakes began over a century ago and intensified since 1950 CE, indicating a regional-scale response to anthropogenic climate warming. Zooplankton in the forest lakes showed asynchronous trajectories, with increased Nr deposition as a significant explanatory factor. Forest lakes with higher dissolved organic carbon (DOC) concentrations partially buffered the impacts of Nr deposition with little structural change, while lakes with low DOC display symptoms of resilience loss related to Nr deposition. Biological community compositional turnover in subalpine lakes has shown marked shifts, equivalent to those of low-elevation lakes strongly affected by direct human impacts. This suggests that local effects override climatic forcing and that lake basin features modified by anthropogenic activity act as basin-specific filters of common forcing. Our results indicate that snow and glacial meltwaters along with nutrient enrichment related to climate warming and atmospheric Nr deposition, represent major threats for lake ecosystems, even in remote areas. We reveal that climate and atmospheric contaminants will further impact ecological conditions and alter aquatic food webs in higher altitude biomes if climate and anthropogenic forcing continue.

Direct and biologically significant interactions of human herpesvirus 8 interferon regulatory factor 1 with STAT3 and Janus kinase TYK2.

Human herpesvirus 8 (HHV-8) encodes four viral interferon regulatory factors (vIRFs) that target cellular IRFs and/or other innate-immune and stress signaling regulators and suppress the cellular response to viral infection and replication. For vIRF-1, cellular protein targets include IRFs, p53, p53-activating ATM kinase, BH3-only proteins, and antiviral signaling effectors MAVS and STING; vIRF-1 inhibits each, with demonstrated or likely promotion of HHV-8 de novo infection and productive replication. Here, we identify direct interactions of vIRF-1 with STAT3 and STAT-activating Janus kinase TYK2 (the latter reported previously by us to be inhibited by vIRF-1) and suppression by vIRF-1 of cytokine-induced STAT3 activation. Suppression of active, phosphorylated STAT3 (pSTAT3) by vIRF-1 was evident in transfected cells and vIRF-1 ablation in lytically-reactivated recombinant-HHV-8-infected cells led to increased levels of pSTAT3. Using a panel of vIRF-1 deletion variants, regions of vIRF-1 required for interactions with STAT3 and TYK2 were identified, which enabled correlation of STAT3 signaling inhibition by vIRF-1 with TYK2 binding, independently of STAT3 interaction. A viral mutant expressing vIRF-1 deletion-variant Δ198-222 refractory for TYK2 interaction and pSTAT3 suppression was severely compromised for productive replication. Conversely, expression of phosphatase-resistant, protractedly-active STAT3 led to impaired HHV-8 replication. Cells infected with HHV-8 mutants expressing STAT3-refractory vIRF-1 deletion variants or depleted of STAT3 displayed reduced vIRF-1 expression, while custom-peptide-promoted STAT3 interaction could effect increased vIRF-1 expression and enhanced virus replication. Taken together, our data identify vIRF-1 targeting and inhibition of TYK2 as a mechanism of STAT3-signaling suppression and critical for HHV-8 productive replication, the importance of specific pSTAT3 levels for replication, positive roles of STAT3 and vIRF-1-STAT3 interaction in vIRF-1 expression, and significant contributions to lytic replication of STAT3 targeting by vIRF-1.

An evaluation of systematic and random errors in ultrasound estimated fetal weight during serial ultrasound.

Introduction: Ultrasound estimated fetal weight is increasingly being used in the monitoring of fetal growth. Large systematic and random errors in estimated fetal weight have been reported; these may have an impact on the accuracy of fetal growth monitoring. The aim of this study was to attempt to evaluate these systematic and random errors by analysis of serial ultrasound data. Methods: Ultrasound measurements and birthweights were retrospectively collected for 100 unselected patients who had undergone serial ultrasound. Birthweights were used to calculate expected fetal growth trajectories using a method for generating growth charts based on customised birthweights. Estimated fetal weight results were then compared with the expected growth trajectories to evaluate systematic and random differences. Results: Incomplete measurement sets were excluded, reducing the number of scans to less than three for 13 subjects. A further 17 subjects with suspected pathological growth trajectories were excluded. The final analysis included 70 subjects with a total of 246 scans. The mean difference between estimated fetal weight and expected weight over three to six scans ranged from -17.5% to 38.3% with a mean of 8.4%, representing the systematic difference. The standard deviation of these differences ranged from 0.4% to 21% with a mean of 4.3%, representing random difference. Conclusion: Systematic and random differences between estimated fetal weight and expected fetal weight are significant and make interpretation of fetal growth difficult. Further improvements to formulae and growth curves are required and audit of fetal measurements is essential to service improvement.

Diagnosing borderline personality disorder: Reports and recommendations from people with lived experience.

Borderline personality disorder (BPD) is a severe mental health condition marked by impairments in self and interpersonal functioning. Stigma from health staff may often result in a reluctance to diagnose, impacting recovery trajectories. Qualitative interviews were conducted with participants (N = 15; M Age = 36.4 years, SD = 7.5; 93.3% female) with lived experience of BPD exploring topics of illness onset, insight, experience of diagnosis and treatment. Qualitative responses were analysed within a co-design framework with a member of the research team who identifies as having a lived experience of BPD. On average, participant symptoms emerged at 12.1 years of age (SD = 6.6 years, range 1.5-27), but diagnoses of BPD were delayed until 30.2 years (SD = 7.8 years, range 18-44) resulting in a 'diagnosis gap' of 18.1 years (SD = 9.6 years, range 3-30). Participant explanations for BPD emergence varied from biological, psychological and social factors. Benefits of diagnosis (e.g., fostering insight, aiding treatment planning and reducing isolation) were contrasted with challenges (e.g., stigma and treatment unavailability). Delay in diagnosis was common, and no participants reported receiving a diagnosis of BPD during their adolescence yet 85% felt they would have benefited from a diagnosis in adolescence. Only a quarter (27%) felt highly supported in the diagnostic process. An ideal four-step diagnosis procedure was outlined based on recommendations from participants with a lived experience; this involved the following: (1) explain the process, (2) assess thoroughly, (3) explore how the features are active in everyday life and (4) link diagnosis to evidence-based treatment planning.

Prevalence and Risk Factors of Neonatal Hyperbilirubinemia in a Semi-Rural Area of the Democratic Republic of Congo: A Cohort Study.

Neonatal hyperbilirubinemia (NH) is a frequent condition that, if left untreated, can lead to neurological disability and death. We assessed the prevalence of NH and associated neonatal and maternal risk factors in 362 mothers and 365 newborns in a semi-rural area of the Democratic Republic of Congo. In addition, we explored the knowledge and practices of mothers regarding this condition. We collected demographic data, anthropometric data, and obstetric and medical anamneses. We examined newborns at birth and at 24, 48, and 72 hours and measured bilirubin at birth in umbilical cord and capillary blood and thereafter in capillary blood. Hemoglobin, hematocrit, ABO group, Rhesus factor, glucose-6-phosphate dehydrogenase (G6PD) deficiency, Hemoglobin S (HbS), and malaria were assessed in mothers and newborns. Among 296 newborns (all time points available), 5.7% developed NH (95% CI: 3.4-9.0) between 24 and 72 hours according to National Institute for Health and Care Excellence (NICE) UK guidelines. There was a significantly higher risk in newborns with G6PD deficiency (homo- and hemizygous adjusted Odd Ratio [aOR]: 21.0, 95% CI: 4.1-105.9), preterm births (aOR: 6.1, 95% CI: 1.4-26.9), newborns with excessive birth weight loss (aOR: 5.8, 95% CI: 1.4-23.2), and hyperbilirubinemia at birth (aOR: 14.8, 95% CI: 2.7-79.6). Newborns with feto-maternal ABO incompatibility and G6PD deficiency had significantly higher bilirubin at birth than others. More than 60% of mothers had adequate knowledge of NH, but compliance with phototherapy in the absence of symptoms was low. Although risk factors for NH are common in this area, prevalence was not high, suggesting a need for better case definition. Implementation of point-of-care devices for diagnosis and awareness programs on risk prevention could help reduce neonatal morbidity and mortality associated with hyperbilirubinemia in these areas.

Evidence and reporting standards in N-of-1 medical studies: a systematic review.

N-of-1 trials, a special case of Single Case Experimental Designs (SCEDs), are prominent in clinical medical research and specifically psychiatry due to the growing significance of precision/personalized medicine. It is imperative that these clinical trials be conducted, and their data analyzed, using the highest standards to guard against threats to validity. This systematic review examined publications of medical N-of-1 trials to examine whether they meet (a) the evidence standards and (b) the criteria for demonstrating evidence of a relation between an independent and an outcome variable per the What Works Clearinghouse (WWC) standards for SCEDs. We also examined the appropriateness of the data analytic techniques in the special context of N-of-1 designs. We searched for empirical journal articles that used N-of-1 design and published between 2013 and 2022 in PubMed and Web of Science. Protocols or methodological papers and studies that did not manipulate a medical condition were excluded. We reviewed 115 articles; 4 (3.48%) articles met all WWC evidence standards. Most (99.1%) failed to report an appropriate design-comparable effect size; neither did they report a confidence/credible interval, and 47.9% reported neither the raw data rendering meta-analysis impossible. Most (83.8%) ignored autocorrelation and did not meet distributional assumptions (65.8%). These methodological problems could lead to significantly inaccurate effect sizes. It is necessary to implement stricter guidelines for the clinical conduct and analyses of medical N-of-1 trials. Reporting neither raw data nor design-comparable effect sizes renders meta-analysis impossible and is antithetical to the spirit of open science.

Distinct hemodynamic and functional connectivity features of fatigue in clinically isolated syndrome and multiple sclerosis: accounting for the confounding effect of concurrent depression symptoms.

PURPOSE: This study aims to identify common and distinct hemodynamic and functional connectivity (FC) features for self-rated fatigue and depression symptoms in patients with clinically isolated syndrome (CIS) and relapsing-remitting multiple sclerosis (RR-MS). METHODS: Twenty-four CIS, 29 RR-MS patients, and 39 healthy volunteers were examined using resting-state fMRI (rs-fMRI) to obtain whole-brain maps of (i) hemodynamic response patterns (through time shift analysis), (ii) FC (via intrinsic connectivity contrast maps), and (iii) coupling between hemodynamic response patterns and FC. Each regional map was correlated with fatigue scores, controlling for depression, and with depression scores, controlling for fatigue. RESULTS: In CIS patients, the severity of fatigue was associated with accelerated hemodynamic response in the insula, hyperconnectivity of the superior frontal gyrus, and evidence of reduced hemodynamics-FC coupling in the left amygdala. In contrast, depression severity was associated with accelerated hemodynamic response in the right limbic temporal pole, hypoconnectivity of the anterior cingulate gyrus, and increased hemodynamics-FC coupling in the left amygdala. In RR-MS patients, fatigue was associated with accelerated hemodynamic response in the insula and medial superior frontal cortex, increased functional role of the left amygdala, and hypoconnectivity of the dorsal orbitofrontal cortex, while depression symptom severity was linked to delayed hemodynamic response in the medial superior frontal gyrus; hypoconnectivity of the insula, ventromedial thalamus, dorsolateral prefrontal cortex, and posterior cingulate; and decreased hemodynamics-FC coupling of the medial orbitofrontal cortex. CONCLUSION: There are distinct FC and hemodynamic responses, as well as different magnitude and topography of hemodynamic connectivity coupling, associated with fatigue and depression in early and later stages of MS.

Conceptual model to inform Legionella-amoebae control, including the roles of extracellular vesicles in engineered water system infections.

Extracellular vesicles (EVs or exosomes) are well described for bacterial pathogens associated with our gastrointestinal system, and more recently as a novel mechanism for environmental persistence, dissemination and infection for human enteric viruses. However, the roles played by EVs in the ancient arms race that continues between amoebae and one of their prey, Legionella pneumophila, is poorly understood. At best we know of intracellular vesicles of amoebae containing a mix of bacterial prey species, which also provides an enhanced niche for bacteriophage infection/spread. Free-living amoeba-associated pathogens have recently been recognized to have enhanced resistance to disinfection and environmental stressors, adding to previously understood (but for relatively few species of) bacteria sequestered within amoebal cysts. However, the focus of the current work is to review the likely impacts of large numbers of respiratory-sized EVs containing numerous L. pneumophila cells studied in pure and biofilm systems with mixed prey species. These encapsulated pathogens are orders of magnitude more resistant to disinfection than free cells, and our engineered systems with residual disinfectants could promote evolution of resistance (including AMR), enhanced virulence and EV release. All these are key features for evolution within a dead-end human pathogen post lung infection. Traditional single-hit pathogen infection models used to estimate the probability of infection/disease and critical environmental concentrations via quantitative microbial risk assessments may also need to change. In short, recognizing that EV-packaged cells are highly virulent units for transmission of legionellae, which may also modulate/avoid human host immune responses. Key data gaps are raised and a previous conceptual model expanded upon to clarify where biofilm EVs could play a role promoting risk as well as inform a more wholistic management program to proactively control legionellosis.

I saw the "bear paw" sign - Massive renal xanthogranulomatous pyelonephritis.

The bear paw sign is a radiologic sign seen on computed tomography (CT) that indicates the development of xanthogranulomatous pyelonephritis (XGP). It refers to the multiple, rim-enhancing, low attenuation renal collections seen in the diffuse form of XGP. The term "bear paw" sign first appeared in the literature in 1989 and has since been widely used to describe this serious, but treatable, pathology.

Leprosy rash precipitated by immunotherapy for suspected inflammatory neuropathy.

Leprosy is a chronic granulomatous infection caused by Mycobacterium leprae complex, causing skin and nerve lesions with potential for permanent disability. Leprosy can be overlooked in Western settings, as it is more prevalent in low-income and middle-income countries. We describe a 38-year-old woman with a 4-year history of progressive numbness of the left hand incorrectly diagnosed as multifocal acquired demyelinating sensory and motor neuropathy on the basis of clinical and neurophysiological findings. Treatment with empirical weekly corticosteroid followed by intravenous immunoglobulin resulted in the sudden development of a widespread rash; we then diagnosed borderline lepromatous leprosy on skin biopsy. We postulate that the immune treatments induced a temporary state of immune tolerance followed by a rebound of a T cell-mediated immune response resulting in a type 1 immunological response.

Comment on Pyrrolizidine Alkaloids and Terpenes from Senecio (Asteraceae): Chemistry and Research Gaps in Africa.

The genus Senecio is one of the largest in Asteraceae. There are thousands of species across the globe, either confirmed or awaiting taxonomic delimitation. While the species are best known for the toxic pyrrolizidine alkaloids that contaminate honeys (as bees select pollen from the species) and teas via lateral transfer and accumulation from adjacent roots of Senecio in the rhizosphere, they are also associated with more serious cases leading to fatality of grazing ruminants or people by contamination or accidental harvesting for medicine. Surprisingly, there are significantly more sesquiterpenoid than pyrrolizidine alkaloid-containing species. The main chemical classes, aside from alkaloids, are flavonoids, cacalols, eremophilanes, and bisabolols, often in the form of furan derivatives or free acids. The chemistry of the species across the globe generally overlaps with the 469 confirmed species of Africa. A small number of species express multiple classes of compounds, meaning the presence of sesquiterpenes does not exclude alkaloids. It is possible that there are many species that express the pyrrolizidine alkaloids, in addition to the cacalols, eremophilanes, and bisabolols. The aim of the current communication is, thus, to identify the research gaps related to the chemistry of African species of Senecio and reveal the possible chemical groups in unexplored taxa by way of example, thereby creating a summary of references that could be used to guide chemical assignment in future studies.

Biodiversity Effects on Human Mental Health via Microbiota Alterations.

The biodiversity hypothesis postulates that the natural environment positively affects human physical and mental health. We evaluate the latest evidence and propose new tools to examine the halobiont environment. We chose to target our review at neuropsychiatric disorders, including depression, anxiety, autism, dementia, multiple sclerosis, etc. because a green prescription (exposure to green spaces) was shown to benefit patients with neuropsychiatric disorders. Specifically, our review consists of three mini reviews on the associations exploring: (1) ecological biodiversity and human microbiota; (2) human microbiota and neuropsychiatric disorders; (3) ecological biodiversity and neuropsychiatric disorders. We conclude that the environment could directly transfer microbes to humans and that human studies support the gut microbiota as part of the pathophysiology of neuropsychiatric disorders. Overall, the results from the three mini reviews consistently support the biodiversity hypothesis. These findings demonstrated the plausibility of biodiversity exerting mental health effects through biophysiological mechanisms instead of psychological mechanisms alone. The idea can be further tested with novel biodiversity measurements and research on the effects of a green prescription.

Lipid lowering effects of the CETP inhibitor obicetrapib in combination with high-intensity statins: a randomized phase 2 trial.

Global guidelines for the management of high-cardiovascular-risk patients include aggressive goals for low-density lipoprotein cholesterol (LDL-C). Statin therapy alone is often insufficient to reach goals and nonstatin options have limitations. Here, we tested the lipid-lowering effects of the cholesteryl ester transfer protein (CETP) inhibitor drug obicetrapib in a randomized, double-blind, placebo-controlled trial in dyslipidaemic patients (n = 120, median LDL-C 88 mg dl-1) with background high-intensity statin treatment (NCT04753606). Over the course of 8 weeks, treatment with 5 mg or 10 mg obicetrapib resulted in a significant decrease as compared with placebo in median LDL-C concentration (by up to 51%; P < 0.0001), the primary trial outcome. As compared with placebo, obicetrapib treatment also significantly (P < 0.0001) decreased apolipoprotein B (by up to 30%) and non-high-density lipoprotein cholesterol (non-HDL-C) concentration (by up to 44%), and significantly (P < 0.0001) increased HDL-C concentration (by up to 165%; the secondary trial outcomes) and had an acceptable safety profile. These results support the potential of obicetrapib to address an unmet medical need for high-cardiovascular-risk patients.

STAT and Janus kinase targeting by human herpesvirus 8 interferon regulatory factor in the suppression of type-I interferon signaling.

Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma (KS)-associated herpesvirus, is involved etiologically in AIDS-associated KS, primary effusion lymphoma (PEL), and multicentric Castleman's disease, in which both viral latent and lytic functions are important. HHV-8 encodes four viral interferon regulatory factors (vIRFs) that are believed to contribute to viral latency (in PEL cells, at least) and/or to productive replication via suppression of cellular antiviral and stress signaling. Here, we identify vIRF-1 interactions with signal transducer and activator of transcription (STAT) factors 1 and 2, interferon (IFN)-stimulated gene factor 3 (ISGF3) cofactor IRF9, and associated signal transducing Janus kinases JAK1 and TYK2. In naturally infected PEL cells and in iSLK epithelial cells infected experimentally with genetically engineered HHV-8, vIRF-1 depletion or ablation, respectively, led to increased levels of active (phosphorylated) STAT1 and STAT2 in IFNß-treated, and untreated, cells during lytic replication and to associated cellular-gene induction. In transfected 293T cells, used for mechanistic studies, suppression by vIRF-1 of IFNß-induced phospho-STAT1 (pSTAT1) was found to be highly dependent on STAT2, indicating vIRF-1-mediated inhibition and/or dissociation of ISGF3-complexing, resulting in susceptibility of pSTAT1 to inactivating dephosphorylation. Indeed, coprecipitation experiments involving targeted precipitation of ISGF3 components identified suppression of mutual interactions by vIRF-1. In contrast, suppression of IFNß-induced pSTAT2 was effected by regulation of STAT2 activation, likely via detected inhibition of TYK2 and its interactions with STAT2 and IFN type-I receptor (IFNAR). Our identified vIRF-1 interactions with IFN-signaling mediators STATs 1 and 2, co-interacting ISGF3 component IRF9, and STAT-activating TYK2 and the suppression of IFN signaling via ISGF3, TYK2-STAT2 and TYK2-IFNAR disruption and TYK2 inhibition represent novel mechanisms of vIRF function and HHV-8 evasion from host-cell defenses.

Phenoplasticity of Essential Oils from Two Species of Piper (Piperaceae): Comparing Wild Specimens and Bi-Generational Monoclonal Cultivars.

This study tested the hypothesis that "clonal chemical heritability is a crucial factor for the conservation of chemical uniformity of Piper essential oils in controlled monoclonal cultivation". We asexually propagated first and second-generation clones of two medicinal and aromatic species, Piper gaudichaudianum Kunth and Piper mollicomum Kunth (Piperaceae), for use as experimental models since they show high chemical plasticity in the wild. Leaves from wild specimens of both species, and their respective cultivated specimens, were hydrodistilled in a Clevenger-type apparatus to produce essential oils (EOs). EOs were chemically characterised by GC-MS and GC-FID. The analysis identified 63 compounds in EO of P. mollicomum, which were predominantly monoterpenes, and 59 in EO of P. gaudichaudianum, which were predominantly sesquiterpenes. Evaluation of chemical diversity and oxi-reduction indices showed a loss of chemical homology across the intergenerational cline. Chemometric analysis indicated higher chemical plasticity between wild and intergenerational specimens of P. mollicomum, than for P. gaudichaudianum. EO compounds were significantly less oxidized throughout the generations in both species. Therefore, while clonal heritability is crucial to chemical homology, significant chemical plasticity is likely to occur when cultivated from wild specimens.