Low 2-Dimensional CD4 T Cell Receptor Affinity for Myelin Sets in Motion Delayed Response Kinetics

T cells recognizing self-peptides that mediate autoimmune disease and those that are responsible for efficacious immunity against pathogens may differ in affinity for antigen due to central and peripheral tolerance mechanisms. Here we utilize prototypical self-reactive (myelin) and viral-specific (LCMV) T cells from T cell receptor (TCR) transgenic mice (2D2 and SMARTA, respectively) to explore affinity differences. The T cells responsive to virus possessed >10,000 fold higher 2D affinity as compared to the self-reactive T cells. Despite their dramatically lower affinity for their cognate ligand, 2D2 T cells respond with complete, albeit delayed, activation (proliferation and cytokine production). SMARTA activation occurs rapidly, achieving peak phosphorylation of p38 (1 minute), Erk (30 minutes), and Jun (3 hours) as well as CD69 and CD25 upregulation (3 and 6 hours, respectively), with a corresponding early initiation of proliferation. 2D2 stimulation with MOG results in altered signaling – no phospho-Erk or phospho-p38 accumulation, significantly delayed activation kinetics of Jun (12 hours), and delayed but sustained SHP-1 activity – as well as delayed CD69 and CD25 expression (12–24 hours), and slow initiation of proliferation. This delay was not intrinsic to the 2D2 T cells, as a more potent antigen with >100-fold increased 2D affinity restored rapid response kinetics in line with those identified for the viral antigen. Taken together, these data demonstrate that time can offset low TCR affinity to attain full activation and suggest a mechanism by which low affinity T cells participate in autoimmune disease

A Widespread Bacterial Type VI Secretion Effector Superfamily Identified Using a Heuristic Approach

SummarySophisticated mechanisms are employed to facilitate information exchange between interfacing bacteria. A type VI secretion system (T6SS) of Pseudomonas aeruginosa was shown to deliver cell wall-targeting effectors to neighboring cells. However, the generality of bacteriolytic effectors and, moreover, of antibacterial T6S remained unknown. Using parameters derived from experimentally validated bacterial T6SS effectors we identified a phylogenetically disperse superfamily of T6SS-associated peptidoglycan-degrading effectors. The effectors separate into four families composed of peptidoglycan amidase enzymes of differing specificities. Effectors strictly co-occur with cognate immunity proteins, indicating that self-intoxication is a general property of antibacterial T6SSs and effector delivery by the system exerts a strong selective pressure in nature. The presence of antibacterial effectors in a plethora of organisms, including many that inhabit or infect polymicrobial niches in the human body, suggests that the system could mediate interbacterial interactions of both environmental and clinical significance

Work-related psychological health among clergywomen in Australia

Drawing on the classic model of balanced affect, the Francis Burnout Inventory conceptualises good work-related psychological health among clergy in terms of negative affect being balanced by positive affect. This paper sets out to explore the relationship between work-related psychological health and psychological type (as assessed by the Francis Psychological-Type Scales) among a sample of 212 Australian clergywomen who completed the National Church Life Survey Form L in 2006. The data supported the internal consistency reliability of the Francis Burnout Inventory and Francis Psychological-Type Scales and found that work-related psychological health was positively related to extraversion and sensing

Mitochondrial respiration - an important therapeutic target in melanoma

The importance of mitochondria as oxygen sensors as well as producers of ATP and reactive oxygen species (ROS) has recently become a focal point of cancer research. However, in the case of melanoma, little information is available to what extent cellular bioenergetics processes contribute to the progression of the disease and related to it, whether oxidative phosphorylation (OXPHOS) has a prominent role in advanced melanoma. In this study we demonstrate that compared to melanocytes, metastatic melanoma cells have elevated levels of OXPHOS. Furthermore, treating metastatic melanoma cells with the drug, Elesclomol, which induces cancer cell apoptosis through oxidative stress, we document by way of stable isotope labeling with amino acids in cell culture (SILAC) that proteins participating in OXPHOS are downregulated. We also provide evidence that melanoma cells with high levels of glycolysis are more resistant to Elesclomol. We further show that Elesclomol upregulates hypoxia inducible factor 1-α (HIF-1α), and that prolonged exposure of melanoma cells to this drug leads to selection of melanoma cells with high levels of glycolysis. Taken together, our findings suggest that molecular targeting of OXPHOS may have efficacy for advanced melanoma. © 2012 Barbi de Moura et al

Space Systems: Emerging Technologies and Operations

SPACE SYSTEMS: EMERGING TECHNOLOGIES AND OPERATIONS is our seventh textbook in a series covering the world of UASs / CUAS/ UUVs. Other textbooks in our series are Drone Delivery of CBNRECy – DEW Weapons: Emerging Threats of Mini-Weapons of Mass Destruction and Disruption (WMDD); Disruptive Technologies with applications in Airline, Marine, Defense Industries; Unmanned Vehicle Systems & Operations On Air, Sea, Land; Counter Unmanned Aircraft Systems Technologies and Operations; Unmanned Aircraft Systems in the Cyber Domain: Protecting USA’s Advanced Air Assets, 2nd edition; and Unmanned Aircraft Systems (UAS) in the Cyber Domain Protecting USA\u27s Advanced Air Assets, 1st edition. Our previous six titles have received considerable global recognition in the field. (Nichols & Carter, 2022) (Nichols et al., 2021) (Nichols R. K. et al., 2020) (Nichols R. et al., 2020) (Nichols R. et al., 2019) (Nichols R. K., 2018) Our seventh title takes on a new purview of Space. Let\u27s think of Space as divided into four regions. These are Planets, solar systems, the great dark void (which fall into the purview of astronomers and astrophysics), and the Dreamer Region. The earth, from a measurement standpoint, is the baseline of Space. It is the purview of geographers, engineers, scientists, politicians, and romantics. Flying high above the earth are Satellites. Military and commercial organizations govern their purview. The lowest altitude at which air resistance is low enough to permit a single complete, unpowered orbit is approximately 80 miles (125 km) above the earth\u27s surface. Normal Low Earth Orbit (LEO) satellite launches range between 99 miles (160 km) to 155 miles (250 km). Satellites in higher orbits experience less drag and can remain in Space longer in service. Geosynchronous orbit is around 22,000 miles (35,000 km). However, orbits can be even higher. UASs (Drones) have a maximum altitude of about 33,000 ft (10 km) because rotating rotors become physically limiting. (Nichols R. et al., 2019) Recreational drones fly at or below 400 ft in controlled airspace (Class B, C, D, E) and are permitted with prior authorization by using a LAANC or DroneZone. Recreational drones are permitted to fly at or below 400 ft in Class G (uncontrolled) airspace. (FAA, 2022) However, between 400 ft and 33,000 ft is in the purview of DREAMERS. In the DREAMERS region, Space has its most interesting technological emergence. We see emerging technologies and operations that may have profound effects on humanity. This is the mission our book addresses. We look at the Dreamer Region from three perspectives:1) a Military view where intelligence, jamming, spoofing, advanced materials, and hypersonics are in play; 2) the Operational Dreamer Region; whichincludes Space-based platform vulnerabilities, trash, disaster recovery management, A.I., manufacturing, and extended reality; and 3) the Humanitarian Use of Space technologies; which includes precision agriculture wildlife tracking, fire risk zone identification, and improving the global food supply and cattle management. Here’s our book’s breakdown: SECTION 1 C4ISR and Emerging Space Technologies. C4ISR stands for Command, Control, Communications, Computers, Intelligence, Surveillance, and Reconnaissance. Four chapters address the military: Current State of Space Operations; Satellite Killers and Hypersonic Drones; Space Electronic Warfare, Jamming, Spoofing, and ECD; and the challenges of Manufacturing in Space. SECTION 2: Space Challenges and Operations covers in five chapters a wide purview of challenges that result from operations in Space, such as Exploration of Key Infrastructure Vulnerabilities from Space-Based Platforms; Trash Collection and Tracking in Space; Leveraging Space for Disaster Risk Reduction and Management; Bio-threats to Agriculture and Solutions From Space; and rounding out the lineup is a chapter on Modelling, Simulation, and Extended Reality. SECTION 3: Humanitarian Use of Space Technologies is our DREAMERS section. It introduces effective use of Drones and Precision Agriculture; and Civilian Use of Space for Environmental, Wildlife Tracking, and Fire Risk Zone Identification. SECTION 3 is our Hope for Humanity and Positive Global Change. Just think if the technologies we discuss, when put into responsible hands, could increase food production by 1-2%. How many more millions of families could have food on their tables? State-of-the-Art research by a team of fifteen SMEs is incorporated into our book. We trust you will enjoy reading it as much as we have in its writing. There is hope for the future.https://newprairiepress.org/ebooks/1047/thumbnail.jp

Cyber-Human Systems, Space Technologies, and Threats

CYBER-HUMAN SYSTEMS, SPACE TECHNOLOGIES, AND THREATS is our eighth textbook in a series covering the world of UASs / CUAS/ UUVs / SPACE. Other textbooks in our series are Space Systems Emerging Technologies and Operations; Drone Delivery of CBNRECy – DEW Weapons: Emerging Threats of Mini-Weapons of Mass Destruction and Disruption (WMDD); Disruptive Technologies with applications in Airline, Marine, Defense Industries; Unmanned Vehicle Systems & Operations On Air, Sea, Land; Counter Unmanned Aircraft Systems Technologies and Operations; Unmanned Aircraft Systems in the Cyber Domain: Protecting USA’s Advanced Air Assets, 2nd edition; and Unmanned Aircraft Systems (UAS) in the Cyber Domain Protecting USA’s Advanced Air Assets, 1st edition. Our previous seven titles have received considerable global recognition in the field. (Nichols & Carter, 2022) (Nichols, et al., 2021) (Nichols R. K., et al., 2020) (Nichols R. , et al., 2020) (Nichols R. , et al., 2019) (Nichols R. K., 2018) (Nichols R. K., et al., 2022)https://newprairiepress.org/ebooks/1052/thumbnail.jp

LC/MS-Based Quantitative Proteomic Analysis of Paraffin-Embedded Archival Melanomas Reveals Potential Proteomic Biomarkers Associated with Metastasis

BACKGROUND: Melanoma metastasis status is highly associated with the overall survival of patients; yet, little is known about proteomic changes during melanoma tumor progression. To better understand the changes in protein expression involved in melanoma progression and metastasis, and to identify potential biomarkers, we conducted a global quantitative proteomic analysis on archival metastatic and primary melanomas. METHODOLOGY AND FINDINGS: A total of 16 metastatic and 8 primary cutaneous melanomas were assessed. Proteins were extracted from laser captured microdissected formalin fixed paraffin-embedded archival tissues by liquefying tissue cells. These preparations were analyzed by a LC/MS-based label-free protein quantification method. More than 1500 proteins were identified in the tissue lysates with a peptide ID confidence level of >75%. This approach identified 120 significant changes in protein levels. These proteins were identified from multiple peptides with high confidence identification and were expressed at significantly different levels in metastases as compared with primary melanomas (q-Value<0.05). CONCLUSIONS AND SIGNIFICANCE: The differentially expressed proteins were classified by biological process or mapped into biological system networks, and several proteins were implicated by these analyses as cancer- or metastasis-related. These proteins represent potential biomarkers for tumor progression. The study successfully identified proteins that are differentially expressed in formalin fixed paraffin-embedded specimens of metastatic and primary melanoma