Metabolic Dependencies in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer with a long-term survival rate under 10%. Available cytotoxic chemotherapies have significant side effects, and only marginal therapeutic efficacy. FDA approved drugs currently used against PDA target DNA metabolism and DNA integrity. However, alternative metabolic targets beyond DNA may prove to be much more effective. PDA cells are forced to live within a particularly severe microenvironment characterized by relative hypovascularity, hypoxia, and nutrient deprivation. Thus, PDA cells must possess biochemical flexibility in order to adapt to austere conditions. A better understanding of the metabolic dependencies required by PDA to survive and thrive within a harsh metabolic milieu could reveal specific metabolic vulnerabilities. These molecular requirements can then be targeted therapeutically, and would likely be associated with a clinically significant therapeutic window since the normal tissue is so well-perfused with an abundant nutrient supply. Recent work has uncovered a number of promising therapeutic targets in the metabolic domain, and clinicians are already translating some of these discoveries to the clinic. In this review, we highlight mitochondria metabolism, non-canonical nutrient acquisition pathways (macropinocytosis and use of pancreatic stellate cell-derived alanine), and redox homeostasis as compelling therapeutic opportunities in the metabolic domain

An experimental investigation into bearing‐induced spindle vibration

This paper describes experiments carried out to investigate the frequency response of a grinding machine tool spindle supported by preloaded angular‐contact ball bearings. The experimental apparatus includes a loading device to simulate grinding head radial loads. The frequency spectra obtained show bands of frequencies associated with the ball passage frequency. The spectra also include bounce and rocking vibration modes of the assembly, where the supporting bearings act as non‐linear springs. Good correlation of the dominant frequencies was obtained with the results of the theoretical models published elsewhere

Using antibodies against P2Y and P2X receptors in purinergic signaling research

The broad expression pattern of the G protein-coupled P2Y receptors has demonstrated that these receptors are fundamental determinants in many physiological responses, including neuromodulation, vasodilation, inflammation, and cell migration. P2Y receptors couple either Gq or Gi upon activation, thereby activating different signaling pathways. Ionotropic ATP (P2X) receptors bind extracellular nucleotides, a signal which is transduced within the P2X protein complex into a cation channel opening, which usually leads to intracellular calcium concentration elevation. As such, this family of proteins initiates or shapes several cellular processes including synaptic transmission, gene expression, proliferation, migration, and apoptosis. The ever-growing range of applications for antibodies in the last 30 years attests to their major role in medicine and biological research. Antibodies have been used as therapeutic tools in cancer and inflammatory diseases, as diagnostic reagents (flow cytometry, ELISA, and immunohistochemistry, to name a few applications), and in widespread use in biological research, including Western blot, immunoprecipitation, and ELISPOT. In this article, we will showcase several of the advances that scientists around the world have achieved using the line of antibodies developed at Alomone Labs for P2Y and P2X receptors

Towards Engineering Fair and Equitable Software Systems for Managing Low-Altitude Airspace Authorizations

Small Unmanned Aircraft Systems (sUAS) have gained widespread adoption across a diverse range of applications. This has introduced operational complexities within shared airspaces and an increase in reported incidents, raising safety concerns. In response, the U.S. Federal Aviation Administration (FAA) is developing a UAS Traffic Management (UTM) system to control access to airspace based on an sUAS's predicted ability to safely complete its mission. However, a fully automated system capable of swiftly approving or denying flight requests can be prone to bias and must consider safety, transparency, and fairness to diverse stakeholders. In this paper, we present an initial study that explores stakeholders' perspectives on factors that should be considered in an automated system. Results indicate flight characteristics and environmental conditions were perceived as most important but pilot and drone capabilities should also be considered. Further, several respondents indicated an aversion to any AI-supported automation, highlighting the need for full transparency in automated decision-making. Results provide a societal perspective on the challenges of automating UTM flight authorization decisions and help frame the ongoing design of a solution acceptable to the broader sUAS community

Predisposing Deleterious Variants in the Cancer-Associated Human Kinases in the Global Populations

Human kinases play essential and diverse roles in the cellular activities of maintaining homeostasis and growth. Genetic mutations in the genes encoding the kinases (or phosphotransferases) have been linked with various types of cancers. In this study, we cataloged mutations in 500 kinases genes in \u3e65,000 individuals of global populations from the Human Genetic Diversity Project (HGDP) and ExAC databases, and assessed their potentially deleterious impact by using the in silico tools SIFT, Polyphen2, and CADD. The analysis highlighted 35 deleterious non-synonymous SNVs in the ExAC and 5 SNVs in the HGDP project. Notably, a higher number of deleterious mutations was observed in the Non-Finnish Europeans (26 SNVs), followed by the Africans (14 SNVs), East Asians (13 SNVs), and South Asians (12 SNVs). The gene set enrichment analysis highlighted NTRK1 and FGFR3 being most significantly enriched among the kinases. The gene expression analysis revealed over-expression of NTRK1 in liver cancer, whereas, FGFR3 was found over-expressed in lung, breast, and liver cancers compared to their expression in the respective normal tissues. Also, 13 potential drugs were identified that target the NTRK1 protein, whereas 6 potential drugs for the FGFR3 target were identified. Taken together, the study provides a framework for exploring the predisposing germline mutations in kinases to suggest the underlying pathogenic mechanisms in cancers. The potential drugs are also suggested for personalized cancer management

MACK-IV, a new version of MACK: a program to calculate nuclear response functions from data in ENDF/B format

MACK-IV calculates nuclear response functions important to the neutronics analysis of nuclear and fusion systems. A central part of the code deals with the calculation of the nuclear response function for nuclear heating more commonly known as the kerma factor. Pointwise and multigroup neutron kerma factors, individual reactions, helium, hydrogen, and tritium production response functions are calculated from any basic nuclear data library in ENDF/B format. The program processes all reactions in the energy range of 0 to 20 MeV for fissionable and nonfissionable materials. The program also calculates the gamma production cross sections and the gamma production energy matrix. A built-in computational capability permits the code to calculate the cross sections in the resolved and unresolved resonance regions from resonance parameters in ENDF/B with an option for Doppler broadening. All energy pointwise and multigroup data calculated by the code can be punched, printed and/or written on tape files. Multigroup response functions (e.g., kerma factors, reaction cross sections, gas production, atomic displacements, etc.) can be outputted in the format of MACK-ACTIVITY-Table suitable for direct use with current neutron (and photon) transport codes

Skeletal Muscle Acute and Chronic Metabolic Response to Essential Amino Acid Supplementation in Hypertriglyceridemic Older Adults

BACKGROUND: Supplementation with essential amino acids (EAAs) + arginine is a promising nutritional approach to decrease plasma triglyceride (TG) concentrations, which are an independent risk factor for ischemic heart disease. OBJECTIVE: The objective of this study was to examine the effects of 8 wk of EAA supplementation on skeletal muscle basal metabolite concentrations and changes in metabolic response to acute EAA intake, with an emphasis on mitochondrial metabolism, in adults with elevated TGs to better understand the mechanisms of lowering plasma TGs. METHODS: Older adults with elevated plasma TG concentrations were given 22 g EAAs to ingest acutely before and after an 8-wk EAA supplementation period. Skeletal muscle biopsy samples were collected before and after acute EAA intake, both pre- and postsupplementation (4 biopsy samples), and targeted metabolomic analyses of organic acids and acylcarnitines were conducted on the specimens. RESULTS: Acute EAA intake resulted in increased skeletal muscle acylcarnitine concentrations associated with oxidative catabolism of the supplement components, with the largest increases found in acylcarnitines of branched-chain amino acid oxidative catabolism, including isovaleryl-carnitine (2200%) and 2-methylbutyryl-carnitine (2400%). The chronic EAA supplementation resulted in a 19% decrease in plasma TGs along with accumulation of long-chain acylcarnitines myristoyl- (90%) and stearoyl- (120%) carnitine in skeletal muscle and increases in succinyl-carnitine (250%) and the late-stage tricarboxylic acid cycle intermediates fumarate (44%) and malate (110%). CONCLUSIONS: Supplementation with EAAs shows promise as an approach for moderate reduction in plasma TGs. Changes in skeletal muscle metabolites suggest incomplete fatty acid oxidation and increased anaplerosis, which suggests a potential bottleneck in fatty acid metabolism

Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells.

Cancer aggressiveness may result from the selective pressure of a harsh nutrient-deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Glucose or glutamine withdrawal resulted in a 5- to 10-fold protective effect with chemotherapy treatment. PDAC xenografts were less sensitive to gemcitabine in hypoglycemic mice compared with hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine (n = 107) with elevated serum glucose levels (HgbA1C \u3e 6.5%) exhibited improved survival. We identified enhanced antioxidant defense as a driver of chemoresistance in this setting. ROS levels were doubled in vitro by either nutrient withdrawal or gemcitabine treatment, but depriving PDAC cells of nutrients before gemcitabine treatment attenuated this effect. Mechanistic investigations based on RNAi or CRISPR approaches implicated the RNA binding protein HuR in preserving survival under nutrient withdrawal, with or without gemcitabine. Notably, RNA deep sequencing and functional analyses in HuR-deficient PDAC cell lines identified isocitrate dehydrogenase 1 (IDH1) as the sole antioxidant enzyme under HuR regulation. HuR-deficient PDAC cells lacked the ability to engraft successfully in immunocompromised mice, but IDH1 overexpression in these cells was sufficient to fully restore chemoresistance under low nutrient conditions. Overall, our findings highlight the HuR–IDH1 regulatory axis as a critical, actionable therapeutic target in pancreatic cancer

Ipsilateral common iliac artery plus femoral artery clamping for inducing sciatic nerve ischemia/reperfusion injury in rats: a reliable and simple method

The aim of this study was to develop a practical model of sciatic ischemia reperfusion (I/R) injury producing serious neurologic deficits and being technically feasible compared with the current time consuming or ineffective models. Thirty rats were divided into 6 groups (n = 5). Animal were anesthetized by using ketamine (50 mg/kg) and xylazine (4 mg/kg). Experimental groups included a sham-operated group and five I/R groups with different reperfusion time intervals (0 h, 3 h, 1 d, 4 d, 7 d). In I/R groups, the right common iliac artery and the right femoral artery were clamped for 3 hrs. Sham-operated animals underwent only laparotomy without induction of ischemia. Just before euthanasia, behavioral scores (based on gait, grasp, paw position, and pinch sensitivity) were obtained and then sciatic nerves were removed for light-microscopy studies (for ischemic fiber degeneration (IFD) and edema). Behavioral score deteriorated among the ischemic groups compared with the control group (p < 0.01), with maximal behavioral deficit occurring at 4 days of reperfusion. Axonal swelling and IFD were found to happen only after 4 and 7 days, respectively. Our observations led to an easy-to-use but strong enough method for inducing and studying I/R injury in peripheral nerves

Physics design of a cold neutron source for KIPT neutron source facility.

Argonne National Laboratory (ANL) of USA and Kharkov Institute of Physics and Technology (KIPT) of Ukraine have been collaborating on the conceptual design development of a neutron source facility. It is based on the use of an electron accelerator driven subcritical (ADS) facility with low enriched uranium fuel, using the existing electron accelerators at KIPT of Ukraine [1]. The neutron source of the subcritical assembly is generated from the interaction of 100-KW electron beam, which has a uniform spatial distribution and the electron energy in the range of 100 to 200 MeV, with a natural uranium target [2]. The main functions of the facility are the production of medical isotopes and the support of the Ukraine nuclear power industry. Neutron beam experiments and material studies are also included. Over the past two-three decades, structures with characteristic lengths of 100 {angstrom} and correspondingly smaller vibrational energies have become increasingly important for both science and technology [3]. The characteristic dimensions of the microstructures can be well matched by neutrons with longer vibrational wavelength and lower energy. In the accelerator-driven subcritical facility, most of the neutrons are generated from fission reactions with energy in the MeV range. They are slowed down to the meV energy range through scattering reactions in the moderator and reflector materials. However, the fraction of neutrons with energies less than 5 meV in a normal moderator spectrum is very low because of up-scattering caused by the thermal motion of moderator or reflector molecules. In order to obtain neutrons with energy less than 5 meV, cryogenically cooled moderators 'cold neutron sources' should be used to slow down the neutrons. These cold moderators shift the neutron energy spectrum down because the thermal motion of moderator molecules as well as the up-scattering is very small, which provides large gains in intensity of low energy neutrons, E &lt; 5 meV. The accelerator driven subcritical facility is designed with a provision to add a cryogenically cooled moderator system. This cold neutron source could provide the neutrons beams with lower energy, which could be utilized in scattering experiment and material structures analysis. This study describes the performed physics analyses to define and characterize the cold neutron source of the KIPT neutron source facility. The cold neutron source is designed to optimize the cold neutron brightness to the experimental instruments outside the radial heavy concrete shield of the facility. Liquid hydrogen or solid methane with 20 K temperature is used as a cold moderator. Monte Carlo computer code MCNPX [4], with ENDF/B-VI nuclear data libraries, is utilized to calculate the cold neutron source performance and estimate the nuclear heat load to the cold moderator. The surface source generation capability of MCNPX code has been used to provide the possibility of analyzing different design configurations and perform design optimization analyses with reasonable computer resources. Several design configurations were analyzed and their performance were characterized and optimized