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Hypoxia is a common feature of most solid tumors, one that favors tumor progression and limits treatment effectiveness. Targeting hypoxia has long been a goal in cancer therapy, by identifying factors that reverse or ameliorate the effects of hypoxia on cancer cells. We, and others, have shown that β-caryophyllene (BCP) exhibits anti-proliferative properties in cancer cells. We have further shown that non-cytotoxic concentrations of BCP affect cholesterol and lipid biosynthesis in hypoxic hBrC cells at both transcriptional and translational levels. This led us to hypothesize that BCP may reverse the hypoxic phenotype in hBrC cells. To test this, we determined the effect of BCP on hypoxic sensitive pathways, including oxygen consumption, glycolysis, oxidative stress, cholesterol and fatty acid biosynthesis, and ERK activation. While each of these studies revealed new information on the regulation by hypoxia and BCP, only the lipidomic studies showed reversal of hypoxic-dependent effects by BCP. These later studies showed that hypoxia-treated samples lowered monounsaturated fatty acid levels, shifting the saturation ratios of the fatty acid pools. This signature was ameliorated by sub-lethal concentrations of BCP, possibly through an effect on the C:16 fatty acid saturation ratios. This is consistent with BCP-induced upregulation of the stearoyl-CoA desaturase (SCD) gene, observed previously. This suggests that BCP may interfere with the lipid signature modulated by hypoxia which could have consequences for membrane biosynthesis or composition, both of which are important for cell replication.

Although the global response to COVID-19 has not been entirely unified, the opportunity arises to assess the impact of regional public health interventions and to classify strategies according to their outcome. Analysis of genetic sequence data gathered over the course of the pandemic allows us to link the dynamics associated with networks of connected individuals with specific interventions. In this study, clusters of transmission were inferred from a phylogenetic tree representing the relationships of patient sequences sampled from December 30, 2019 to April 17, 2020. Metadata comprising sampling time and location were used to define the global behavior of transmission over this earlier sampling period, but also the involvement of individual regions in transmission cluster dynamics. Results demonstrate a positive impact of international travel restrictions and nationwide lockdowns on global cluster dynamics. However, residual, localized clusters displayed a wide range of estimated initial secondary infection rates, for which uniform public health interventions are unlikely to have sustainable effects. Our findings highlight the presence of so-called “super-spreaders”, with the propensity to infect a larger-than-average number of people, in countries, such as the USA, for which additional mitigation efforts targeting events surrounding this type of spread are urgently needed to curb further dissemination of SARS-CoV-2.

Background. Despite improvements in antiretroviral therapy, human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) remain prevalent in subjects undergoing therapy. HAND significantly affects individuals’ quality of life, as well as adherence to therapy, and, despite the increasing understanding of neuropathogenesis, no definitive diagnostic or prognostic marker has been identified.Results. We investigated transcriptomic profiles in frontal cortex tissues of Simian immunodeficiency virus (SIV)-infected Rhesus macaques sacrificed at different stages of infection. Gene expression was compared among SIV-infected animals (n=11), with or without CD8+ lymphocyte depletion, based on detectable (n=6) or non-detectable (n=5) presence of the virus in frontal cortex tissues. S ignificant enrichment in activation of monocyte and macrophage cellular pathways was found in animals with detectable brain infection, independently from CD8+ lymphocyte depletion . In addition, transcripts of four poly (ADP-ribose) polymerases ( PARPs) were up-regulated in the frontal cortex, which was confirmed by real-time polymerase chain reaction.Conclusions. Our results shed light on involvement of PARPs in SIV infection of the brain and their role in SIV-associated neurodegenerative processes. Inhibition of PARPs may provide an effective novel therapeutic target for HIV-related neuropathology .

BackgroundDespite improvements in antiretroviral therapy, human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) remain prevalent in subjects undergoing therapy. HAND significantly affects individuals’ quality of life, as well as adherence to therapy, and, despite the increasing understanding of neuropathogenesis, no definitive diagnostic or prognostic marker has been identified.ResultsWe investigated transcriptomic profiles in frontal cortex tissues of Simian immunodeficiency virus (SIV)-infected Rhesus macaques sacrificed at different stages of infection. Gene expression was compared among SIV-infected animals (n=11), with or without CD8+ lymphocyte depletion, based on detectable (n=6) or non-detectable (n=5) presence of the virus in frontal cortex tissues. Significant enrichment in activation of monocyte and macrophage cellular pathways was found in animals with detectable brain infection, independently from CD8+ lymphocyte depletion. In addition, transcripts of four poly (ADP-ribose) polymerases (PARPs) were up-regulated in the frontal cortex, which was confirmed by real-time polymerase chain reaction.ConclusionsOur results shed light on involvement of PARPs in SIV infection of the brain and their role in SIV-associated neurodegenerative processes. Inhibition of PARPs may provide an effective novel therapeutic target for HIV-related neuropathology.

β-caryophyllene (BCP) exhibits anti-proliferative properties in cancer cells. Here, we examine the hypothesis that BCP induces membrane remodeling. Our data show that high concentrations of BCP increase membrane permeability of human breast cells (hBrC) causing detachment and cell death. At a sub-lethal concentration of BCP, we show that BCP induces a striking upregulation of genes involved in cholesterol biosynthesis, including the gene that encodes for HMGCoA reductase (HMGCR), the rate-determining step in cholesterol biosynthesis. In addition, stearoyl-CoA desaturase (SCD) is also upregulated which would lead to the enhanced formation of monounsaturated fatty acids, specifically oleate and palmitoleate from stearoyl CoA and palmitoyl CoA, respectively. These fatty acids are major components of membrane phospholipids and cholesterol esters. Together, these data suggest that cells respond to BCP by increasing the synthesis of components found in membranes. These responses could be viewed as a repair mechanism and/or as a mechanism to mount resistance to the cytotoxic effect of BCP. Blocking HMGCR activity enhances the cytotoxicity of BCP, suggesting that BCP may provide an additional therapeutic tool in controlling breast cancer cell growth.

Model-based design is an approach that aims to establish a framework for complex embedded systems by incorporating graphical and/or textual high-level programming and integrated code generation and simulation tools; during the early phases of model-based design, an executable specification of the intended functionality of the embedded system is also generated. With a parallel proposal, a recent discipline that has received a great deal of attention for product concept and manufacture is virtual prototyping; with virtual prototyping, a visual mockup of the product is built for specification and validation purposes during the early stages of the product design flow. This paper proposes the joint use of virtual prototyping and model-based design for the graphical validation of a sensor-driven plant and for the correct functionality of the embedded controller of the plant; this approach is further supported by a variation of a processor-in-the-loop simulation.

Metoclopramide has been shown to stimulate motility of the gastrointestinal tract, including the esophagus. The authors therefore tested the effect of intravenous injections of metoclopramide on the sphincteric pressure and esophageal motility in 14 patients with esophageal dysfunction due to progressive systemic sclerosis (PSS). Isotonic saline similarly injected in a control period in 7 of the patients showed no effect. None of the 14 patients had a detectable pressure zone at the sphincteric area in basal conditions, but following the injection of metoclopramide, one appeared in 7 patients. Metoclopramide also caused the appearance of pressure waves in 5 of 11 patients who had aperistalsis, and caused up to a three fold increase in the amplitude of the pressure waves in the 3 patients who had hypomotility of the esophagus.

Esophageal monometric studies were done in 10 unselected patients with Sjögren's syndrome, not associated with other connective tissue or chronic active hepatic disease. Nine of the patients revealed abnormal esophageal motility, consisting of absent or decreased contractility in the upper third of the esophagus. In four patients, the dysfunction also extended to other portions of the organ. Dryness of the mouth and oropharynx, or mucosal atrophy, does not explain these findings. The uniform pattern of the esophageal dysfunction found in patients with primary Sjögren's syndrome, which differs from the patterns of involvement observed in other connective tissue diseases, suggests that primary Sjögren's syndrome is probably a distinct entity.

Metoclopramide has been shown to stimulate motility of the gastrointestinal tract, including the esophagus. The authors therefore tested the effect of intravenous injections of metoclopramide on the sphincteric pressure and esophageal motility in 14 patients with esophageal dysfunction due to progressive systemic sclerosis (PSS). Isotonic saline similarly injected in a control period in 7 of the patients showed no effect. None of the 14 patients had a detectable pressure zone at the sphincteric area in basal conditions, but following the injection of metoclopramide, one appeared in 7 patients. Metoclopramide also caused the appearance of pressure waves in 5 of 11 patients who had aperistalsis, and caused up to a three fold increase in the amplitude of the pressure waves in the 3 patients who had hypomotility of the esophagus.

Esophageal manometric studies made in 50 unselected patients with systemic lupus erythematosus disclosed abnormalities in 16. Absent or abnormally low contractions were found at the upper third in 7, at the lower two-thirds in 3, in the entire esophagus in 2, at the lower esophageal sphincter in 2, and at the lower two-thirds plus the lower sphincter in the other 2. There was no relationship between the presence of esophageal dysfunction and activity, duration, or treatment of lupus at the time of the study. Esophageal motor disturbances are part of the spectrum of systemic lupus erythematosus.