With the increased assimilation of technology into all aspects of everyday life, rootkits pose a credible threat to individuals, corporations, and governments. Using various techniques, rootkits can ...infect systems and remain undetected for extended periods of time. This threat necessitates the careful consideration of real-time detection solutions. Behavioral detection techniques allow for the identification of rootkits with no previously recorded signatures. This research examines a variety of machine learning algorithms, including Nearest Neighbor, Decision Trees, Neural Networks, and Support Vector Machines, and proposes a behavioral detection method based on low yield CPU power consumption. The method is evaluated on Windows 7, Windows 10, Ubuntu Desktop, and Ubuntu Server operating systems along with employing four different rootkits. Relevant features within the data are calculated and the overall best performing algorithms are identified. A nested neural network is then applied that enables highly accurate data classification. Our results present a viable method of rootkit detection that can operate in real-time with minimal computational and space complexity.
A retrospective review of medical records for all pediatric parapneumonic empyema (PPE) patients admitted to our hospital from 1996 to 2006 revealed that PPE increased 5-fold in the post-heptavalent ...pneumococcal conjugate vaccine (PCV7) period (2001-2005) relative to the pre-PCV7 period (1996-2000), from 13 cases to 65. Most of this increase was associated with culture-negative empyema, which accounted for 61% of all post-2000 cases; 19% was culture-positive pneumococcal empyema. Our analysis indicates that non-PCV7 serotypes became more prevalent at our institution after introduction of the vaccine.
► The COMM domain of COMMD1 mediates binding to δENaC. ► COMMD1 reduces the cell surface population of δENaC. ► COMMD1 increases the population of δENaC–ubiquitin. ► Both endogenous and transfected ...δENaC localize with COMMD1 and transferrin suggesting they are located in early/recycling endosomes.
The delta subunit of the epithelial sodium channel (δENaC) is a member of the ENaC/degenerin family of ion channels. δENaC is distinct from the related α-, β- and γENaC subunits, known for their role in sodium homeostasis and blood pressure control, as δENaC is expressed in brain neurons and activated by external protons. COMMD1 (copper metabolism Murr1 domain 1) was previously found to associate with and downregulate δENaC activity. Here, we show that COMMD1 interacts with δENaC through its COMM domain. Co-expression of δENaC with COMMD1 significantly reduced δENaC surface expression, and led to an increase in δENaC ubiquitination. Immunocytochemical and confocal microscopy studies show that COMMD1 promoted localization of δENaC to the early/recycling endosomal pool where the two proteins were localized together. These results suggest that COMMD1 downregulates δENaC activity by reducing δENaC surface expression through promoting internalization of surface δENaC to an intracellular recycling pool, possibly via enhanced ubiquitination.
Abstract Interneurons expressing the calcium-binding protein parvalbumin (PV) are a critical component of the inhibitory circuitry of the basolateral nuclear complex (BLC) of the mammalian amygdala. ...These neurons form interneuronal networks interconnected by chemical and electrical synapses, and provide a strong perisomatic inhibition of local pyramidal projection neurons. Immunohistochemical studies in rodents have shown that most parvalbumin-positive (PV+) cells are GABAergic interneurons that co-express the calcium-binding protein calbindin (CB), but exhibit no overlap with interneuronal subpopulations containing the calcium-binding protein calretinin (CR) or neuropeptides. Despite the importance of identifying interneuronal subpopulations for clarifying the major players in the inhibitory circuitry of the BLC, very little is known about these subpopulations in primates. Therefore, in the present investigation dual-labeling immunofluorescence histochemical techniques were used to characterize PV+ interneurons in the basal and lateral nuclei of the monkey amygdala. These studies revealed that 90–94% of PV+ neurons were GABA+, depending on the nucleus, and that these neurons constituted 29–38% of the total GABAergic population. CB+ and CR+ interneurons constituted 31–46% and 23–27%, respectively, of GABAergic neurons. Approximately one quarter of PV+ neurons contained CB, and these cells constituted one third of the CB+ interneuronal population. There was no colocalization of PV with the neuropeptides somatostatin or cholecystokinin, and virtually no colocalization with CR. These data indicate that the neurochemical characteristics of the PV+ interneuronal subpopulation in the monkey BLC are fairly similar to those seen in the rat, but there is far less colocalization of PV and CB in the monkey. These findings suggest that PV+ neurons are a discrete interneuronal subpopulation in the monkey BLC and undoubtedly play a unique functional role in the inhibitory circuitry of this brain region.
The Toronto Extremity Salvage Score (TESS) and the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) are both utilized to measure patient-reported ...outcomes in adults with musculoskeletal oncologic conditions. However, the relationship between them has not been studied. We sought to describe a link between Lower Extremity (LE) TESS and PROMIS Physical Function (PF) scores, as well as between LE TESS and Pain Interference (PI) scores, to develop a method for converting scores between TESS and PROMIS and to examine whether TESS and PROMIS captured differences in pain and function between clinically relevant subgroups in our population.
Our study population consisted of 125 adult patients who underwent surgical treatment of a lower-extremity musculoskeletal tumor at a single sarcoma center between December 2015 and October 2018. The LE TESS questionnaire was administered to patients via paper and the PROMIS PF and PI were administered via iPad at a preoperative appointment. The relationship between LE TESS and PROMIS measures was analyzed with use of generalized linear modeling. Subgroup analyses were performed with a 2-tailed t test or 1-way analysis of variance.
PROMIS PF had a very strong positive correlation with LE TESS (r = 0.83) and was related through the following equation:
= 0.00294 × (
)
+ 22.6. PROMIS PI had a strong negative correlation with LE TESS (r = -0.77) and was related through the following equation:
= -0.00259 × (
)
+ 73.8. PROMIS PF and PI performed similarly to LE TESS across multiple patient subgroups and captured the expected differences between subgroups.
LE TESS and PROMIS PF appeared to measure similar information in patients with an orthopaedic oncologic condition. Moreover, PROMIS PI scores were strongly correlated with functional disability as measured with the LE TESS. Understanding the relationship between TESS and PROMIS will allow the comparison and combination of data for both clinical and research purposes.
Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Background and Purpose
Intrathecally (i.t.) administered nociceptin/orphanin FQ (N/OFQ) evokes antinociceptive effects in rodents. Recent studies in monkeys demonstrated that i.t. co‐application of ...N/OFQ and morphine elicits synergistic antinociceptive actions suggesting mixed N/OFQ peptide (NOP) and μ opioid receptor agonists as innovative spinal analgesics. Thus, novel N/OFQ related peptides were synthesized in order to identify and pharmacologically characterize a mixed NOP/ μ opioid receptor agonist.
Experimental Approach
The following in vitro assays were used: calcium mobilization in cells expressing the human NOP or classical opioid receptors and chimeric G proteins, receptor and 35S‐GTPγS binding, 35S‐GTPγS binding in rat spinal cord membranes, guinea pig ileum bioassay. In vivo experiments were performed in monkeys using the tail withdrawal assay.
Key Results
From calcium mobilization studies Dmt1N/OFQ(1–13)‐NH2 was selected as the most potent and least selective compound. The mixed NOP/opioid full agonist activity and high affinity of Dmt1N/OFQ(1–13)‐NH2 was confirmed at human recombinant receptors in receptor binding, calcium mobilization and/or 35S‐GTPγS binding studies, at rat spinal cord receptors in 35S‐GTPγS binding experiments, and at guinea pig receptors inhibiting neurogenic contractions in the ileum. In vivo in the tail withdrawal assay in monkeys i.t. Dmt1N/OFQ(1–13)‐NH2 was able to elicit robust and long‐lasting antinociceptive effects.
Conclusions and Implications
Collectively, these results demonstrate that Dmt1N/OFQ(1–13)‐NH2 behaves as NOP/opioid receptor universal agonist and substantiate the suggestion that such mixed ligands are worthy of development as innovative spinal analgesics.
Vertebrates possess two paralogs of cytochrome c oxidase (COX) subunit 4: a ubiquitous COX4-1 and a hypoxia-linked COX4-2. Mammalian COX4-2 is thought to have a role in relation to fine-tuning ...metabolism in low oxygen levels, conferred through both structural differences in the subunit protein structure and regulatory differences in the gene. We sought to elucidate the pervasiveness of this feature across vertebrates. The ratio of COX4-2/4-1 mRNA is generally low in mammals, but this ratio was higher in fish and reptiles, particularly turtles. The COX4-2 gene appeared unresponsive to low oxygen in nonmammalian models (zebrafish, goldfish, tilapia, anoles, and turtles) and fish cell lines. Reporter genes constructed from the amphibian and reptile homologues of the mammalian oxygen-responsive elements and hypoxia-responsive elements did not respond to low oxygen. Unlike the rodent ortholog, the promoter of goldfish COX4-2 did not respond to hypoxia or anoxia. The protein sequences of the COX4-2 peptide showed that the disulfide bridge seen in human and rodent orthologs would be precluded in other mammalian lineages and lower vertebrates, all of which lack the requisite pair of cysteines. The coordinating ligands of the ATP-binding site are largely conserved across mammals and reptiles, but in Xenopus and fish, sequence variations may disrupt the ability of the protein to bind ATP at this site. Collectively, these results suggest that many of the genetic and structural features of COX4-2 that impart responsiveness and benefits in hypoxia may be restricted to the Euarchontoglires lineage that includes primates, lagomorphs, and rodents.
Horizontal gene transfer (HGT) confers the rapid acquisition of novel traits and is pervasive throughout microbial evolution. Despite the central role of HGT, the evolutionary forces that drive the ...dynamics of HGT alleles in evolving populations are poorly understood. Here, we show that HGT alters the evolutionary dynamics of genetic variation, so that deleterious genetic variants, including antibiotic resistance genes, can establish in populations without selection. We evolve antibiotic-sensitive populations of the human pathogen Helicobacter pylori in an environment without antibiotic but with HGT from an antibiotic-resistant isolate of H. pylori. We find that HGT increases the rate of adaptation, with most horizontally transferred genetic variants establishing at a low frequency in the population. When challenged with antibiotic, this low-level variation potentiates adaptation, with HGT populations flourishing in conditions where nonpotentiated populations go extinct. By extending previous models of evolution under HGT, we evaluated the conditions for the establishment and spread of HGT-acquired alleles into recipient populations. We then used our model to estimate parameters of HGT and selection from our experimental evolution data. Together, our findings show how HGT can act as an evolutionary force that facilitates the spread of nonselected genetic variation and expands the adaptive potential of microbial populations.
Maize-legume intercropping is a fundamental component of mixed farming systems in the mid-hills of Nepal. However, its productivity is constrained by several biophysical and social factors, and ...limited adoption of proven agricultural innovations. In this study, we assessed the productivity impact of a selection of relevant agricultural innovations and changes in the associated perceptions of farmers through a series of two-year participatory on-farm trials. The evaluated innovations resulted in higher yields as compared to farmers' current practices. The active involvement of farmers enlarged our understanding of underlying decision-making factors to adopt or non-adopt agricultural innovations. Additionally, the in-depth farmer engagement in our onfarm trials positively influenced farmer perceptions of the innovations and their interest to adopt the agricultural innovations. Yet, farmers final decisions to adopt some of the evaluated innovations were limited by a host of factors including labour scarcity, the availability of inputs, and by cultural preferences despite the increased yields. This was particularly true for low and medium resource-endowed farmers. This study shows the importance of active farmer participation and context-specific design of research and development projects aiming for local impact.
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