The roles of poly(ADP-ribose)-metabolizing enzymes in alkylation-induced cell death

Abstract.: Poly(ADP-ribose) (PAR) has been identified as a DNA damage-inducible cell death signal upstream of apoptosis-inducing factor (AIF). PAR causes the translocation of AIF from mitochondria to the nucleus and triggers cell death. In living cells, PAR molecules are subject to dynamic changes pending on internal and external stress factors. Using RNA interference (RNAi), we determined the roles of poly(ADP-ribose) polymerases-1 and -2 (PARP-1, PARP-2) and poly(ADP-ribose) glycohydrolase (PARG), the key enzymes configuring PAR molecules, in cell death induced by an alkylating agent. We found that PARP-1, but not PARP-2 and PARG, contributed to alkylation-induced cell death. Likewise, AIF translocation was only affected by PARP-1. PARP-1 seems to play a major role configuring PAR as a death signal involving AIF translocation regardless of the death pathway involve

Village Water Ozonation System

Safe drinking water is something that all humans need. People around the globe face issues like limited access to water, water scarcity, and contamination of their water supply. Alleviating global water-related illnesses and deaths remains a prevailing challenge to overcome. With this in mind, the Village Water Ozonation System (VWOS) team works with communities to increase their access to safe drinking water. In the past few years, VWOS has had the privilege of walking alongside our partner communities in Mexico, Pakistan, and Nicaragua to develop sustainable drinking water solutions. Through collaborations with several Christian organizations such as Forward Edge International in Mexico, Full Gospel Assemblies Bible College of Pakistan and, Friends in Action International in Nicaragua, the team has acquired an increased awareness of drinking water needs and issues across the world. Over this past academic year, the team has focused on completing a design for a church in Oaxaca, Mexico where water will be drawn from a polluted well. The VWOS design includes accessing the well, purifying the water to a drinkable standard, and providing the option of utility water from the same well. The team has also been designing and testing for a client in Pakistan who has arsenic in their water source. The team has tested and designed in order to remove the arsenic from the source. Implementation for these two projects will be in the near future. Lastly, the team has begun investigation on removal of salt in a water source for a client in Nicaragua.https://mosaic.messiah.edu/engr2020/1013/thumbnail.jp

New synthetic strategies for xanthene-dye-appended cyclodextrins

Xanthene dyes can be appended to cyclodextrins via an ester or amide bridge in order to switch the fluorescence on or off. This is made possible through the formation of nonfluorescent lactones or lactams as the fluorophore can reversibly cyclize. In this context we report a green approach for the synthesis of switchable xanthene-dye-appended cyclodextrins based on the coupling agent 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM). By using 6-monoamino-β-cyclodextrin and commercially available inexpensive dyes, we prepared rhodamine- and fluorescein-appended cyclodextrins. The compounds were characterized by NMR and IR spectroscopy and MS spectrometry, their UV–vis spectra were recorded at various pH, and their purity was determined by capillary electrophoresis. Two potential models for the supramolecular assembly of the xanthene-dye-appended cyclodextrins were developed based on the set of data collected by the extensive NMR characterization

The roles of poly(ADP-ribose)-metabolizing enzymes in alkylation-induced cell death

Poly(ADP-ribose) (PAR) has been identified as a DNA damage-inducible cell death signal upstream of apoptosis-inducing factor (AIF). PAR causes the translocation of AIF from mitochondria to the nucleus and triggers cell death. In living cells, PAR molecules are subject to dynamic changes pending on internal and external stress factors. Using RNA interference (RNAi), we determined the roles of poly(ADP-ribose) polymerases-1 and -2 (PARP-1, PARP-2) and poly(ADP-ribose) glycohydrolase (PARG), the key enzymes configuring PAR molecules, in cell death induced by an alkylating agent. We found that PARP-1, but not PARP-2 and PARG, contributed to alkylation-induced cell death. Likewise, AIF translocation was only affected by PARP-1. PARP-1 seems to play a major role configuring PAR as a death signal involving AIF translocation regardless of the death pathway involved

Hamstring stretch reflex:could it be a reproducible objective measure of functional knee stability?"

Background: The anterior cruciate ligament (ACL) plays an important role in anterior knee stability by preventing anterior translation of the tibia on the femur. Rapid translation of the tibia with respect to the femur produces an ACL-hamstring stretch reflex which may provide an object measure of neuromuscular function following ACL injury or reconstruction. The aim of this study was to determine if the ACL-hamstring stretch reflex could be reliably and consistently obtained using the KT-2000 arthrometer.  Methods: A KT-2000 arthrometer was used to translate the tibia on the femur while recording the electromyography over the biceps femoris muscle in 20 participants, all with intact ACLs. In addition, a sub-group comprising 4 patients undergoing a knee arthroscopy for meniscal pathology, were tested before and after anaesthetic and with direct traction on the ACL during arthroscopy. The remaining 16 participants underwent testing to elicit the reflex using the KT-2000 only.  Results: A total number of 182 trials were performed from which 70 trials elicited stretch reflex (38.5 %). The mean onset latency of the hamstring stretch reflexes was 58.9 ± 17.9 ms. The average pull force was 195 ± 47 N, stretch velocity 48 ± 35 mm/s and rate of force 19.7 ± 6.4 N/s. Conclusions Based on these results, we concluded that the response rate of the anterior cruciate ligament-hamstring reflex is too low for it to be reliably used in a clinical setting, and thus would have limited value in assessing the return of neuromuscular function following ACL injuries

Potentiation of brain stimulation reward by morphine: effects of neurokinin-1 receptor antagonism

The abuse potential of opioids may be due to their reinforcing and rewarding effects, which may be attenuated by neurokinin-1 receptor (NK1R) antagonists

Orexin-1 receptor antagonism does not reduce the rewarding potency of cocaine in Swiss–Webster mice

The orexin family of hypothalamic neuropeptides has been implicated in reinforcement mechanisms relevant to both food and drug reward. Previous behavioral studies with antagonists at the orexin A-selective receptor, OX1, have demonstrated its involvement in behavioral sensitization, conditioned place-preference, and self-administration of drugs of abuse. Adult male Swiss-Webster mice were implanted with stimulating electrodes to the lateral hypothalamus and trained to perform intracranial self-stimulation (ICSS). The effects of the OX1-selective antagonist SB 334867 on brain stimulation-reward (BSR) and cocaine potentiation of BSR were measured. SB 334867 (10 – 30 mg/kg, i.p.) alone had no effect on ICSS performance or BSR threshold. Cocaine (1.0 – 30 mg/kg i.p.) dose-dependently potentiated BSR, measured as lowering of BSR threshold. This effect was not blocked by 30 mg/kg SB 334867 at any cocaine dose tested. In agreement with previous reports, SB 334867 resulted in a reduction of body weight 24 hours after acute administration. Based on these data, it is concluded that orexins acting at OX1 do not contribute to BSR; and are not involved in the reward-potentiating actions of cocaine on BSR. The data are discussed in the context of prior findings of SB 334867 effects on drug-seeking and drug-consuming behaviors

A Novel Mutation in the Upstream Open Reading Frame of the CDKN1B Gene Causes a MEN4 Phenotype

PubMed ID: 23555276This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Different Contributions of Dopamine D1 and D2 Receptor Activity to Alcohol Potentiation of Brain Stimulation Reward in C57BL/6J and DBA/2J Mice

C57BL/6J (C57) and DBA/2J (DBA) mice respond differently to drugs that affect dopamine systems, including alcohol. The current study compared effects of D1 and D2 receptor agonists and antagonists, and the interaction between D1/D2 antagonists and alcohol, on intracranial self-stimulation in male C57 and DBA mice to determine the role of dopamine receptors in the effects of alcohol on brain stimulation reward (BSR). In the initial strain comparison, dose effects on BSR thresholds and maximum operant response rates were determined for the D1 receptor agonist SKF-82958 (±-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.1–0.56 mg/kg) and antagonist SCH 23390 (+-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride; 0.003–0.056 mg/kg), and the D2 receptor agonist quinpirole (0.1–3.0 mg/kg) and antagonist raclopride (0.01–0.56 mg/kg). For the alcohol interaction, SCH 23390 (0.003 mg/kg) or raclopride (0.03 mg/kg) was given before alcohol (0.6–2.4 g/kg p.o.). D1 antagonism dose-dependently elevated and SKF-82958 dose-dependently lowered BSR threshold in both strains; DBA mice were more sensitive to SKF-82958 effects. D2 antagonism dose-dependently elevated BSR threshold only in C57 mice. Low doses of quinpirole elevated BSR threshold equally in both strains, whereas higher doses of quinpirole lowered BSR threshold only in C57 mice. SCH 23390, but not raclopride, prevented lowering of BSR threshold by alcohol in DBA mice. Conversely, raclopride, but not SCH 23390, prevented alcohol potentiation of BSR in C57 mice. These results extend C57 and DBA strain differences to D1/D2 sensitivity of BSR, and suggest differential involvement of D1 and D2 receptors in the acute rewarding effects of alcohol in these two mouse strains