The Effect of Dopa on the Spinal Cord. 8. Presynaptic and “Remote” Inhibition of Transmission from Ia Afferents to Alpha Motoneurones

In unanesthetized spinal cats, injected with l-DOPA, intra-axonal recording was used to investigate the primary afferent depolarization (PAD) evoked in different species of afferents by volleys in the flexor reflex afferents (FRA). It was confirmed that a late PAD is evoked in la afferents and usually not in Ib or cutaneous afferents. Some late PAD was observed in a few group II muscle afferents. Intracellular recording from motoneurones revealed a considerable depression of the Ia EPSP during the late PAD evoked from the FRA after DOPA, but it was diffkult to attribute this entirely to the PAD in Ia afferents since there was also a late postsynaptic conductance increase in the motoneurones. A further analysis was made on acute spinal cats not injected with DOPA, in which a late P.4D sometimes is evoked by FR24 volleys, without the late postsynaptic soma effects in motoneurones. The marked depression of the Ia EPSP evoked from the FRA under these conditions has a longer duration than the PAD in la afferent terminals. It is postulated that two mechanisms contribute to the Ia EPSP depression, presynaptic inhibition and “remote inhibition”; the latter action persisting after the repolarization of Ia afferents. The results are discussed in relation to reflex regulation of stepping.     

Altered chromatin landscape in circulating T follicular helper and regulatory cells following grass pollen subcutaneous and sublingual immunotherapy

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Synthesis and Anti-Chlamydial Activity of Substituted N-Benzylanilines

Pharmaceutical Chemistry Journal - Eleven substituted N-benzylanilines were synthesized. Their anti-chlamydial activity was studied. A water-soluble hydrochloride was prepared from one of the lead...     

Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase

Soluble epoxide hydrolase (sEH) is inhibited by electrophilic lipids by their adduction to Cys521 proximal to its catalytic center. This inhibition prevents hydrolysis of the enzymes’ epoxyeicosatrienoic acid (EET) substrates, so they accumulate inducing vasodilation to lower blood pressure (BP). We generated a Cys521Ser sEH redox-dead knockin (KI) mouse model that was resistant to this mode of inhibition. The electrophilic lipid 10-nitro-oleic acid (NO₂-OA) inhibited hydrolase activity and also lowered BP in an angiotensin II-induced hypertension model in wild-type (WT) but not KI mice. Furthermore, EET/dihydroxy-epoxyeicosatrienoic acid isomer ratios were elevated in plasma from WT but not KI mice following NO₂-OA treatment, consistent with the redox-dead mutant being resistant to inhibition by lipid electrophiles. sEH was inhibited in WT mice fed linoleic acid and nitrite, key constituents of the Mediterranean diet that elevates electrophilic nitro fatty acid levels, whereas KIs were unaffected. These observations reveal that lipid electrophiles such as NO₂-OA mediate antihypertensive signaling actions by inhibiting sEH and suggest a mechanism accounting for protection from hypertension afforded by the Mediterranean diet.Soluble epoxide hydrolase (sEH) has a conserved cysteine (Cys521) proximal to its catalytic center. This cysteine can undergo Michael addition with electrophilic lipids, which inhibits hydrolysis of the enzyme’s epoxyeicosatrienoic acid (EET) substrates (1). This in turn elevates EET levels, which mediate blood vessel dilation and lowers blood pressure (BP), especially in the setting of hypertension (2, 3). Diverse sEH inhibitors limit injury in a variety of diseases (4), providing broad cardiovascular protection (5) against hypertension (6, 7), ischemia and reperfusion injury (8, 9), hypertrophy, and heart failure (10), as well as inflammation (11, 12). Consistent with the therapeutic potential of hydrolase inhibitors, sEH null mice are protected from pathological interventions (13). Conversely, genetic alterations that promote enhanced hydrolase activity are a risk factor for human heart failure (14).The endogenous lipid electrophile 10-nitrooctadec-9-enoic acid (nitro-oleic acid, NO₂-OA) inhibits sEH in vitro (1). NO₂-OA and other fatty acid nitroalkenes appear to signal via pleiotropic mechanisms including targeting and activating peroxisome proliferator-activated receptor gamma (PPARγ), the Kelch-like erythroid cell-derived protein with CNC homology (EHC)-associated protein-1 (Keap1), and nuclear factor (erythroid-derived)-like-2 (Nrf2)-regulated antioxidant response genes and inhibiting proinflammatory gene expression regulated by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) (15, 16). Nitroalkenes are produced by radical addition of nitrogen dioxide (·NO₂) to one or more of the olefinic carbons of an unsaturated fatty acid. Nitrogen dioxide is both a product of oxidative inflammatory reactions involving nitric oxide (NO) and nitrite and the acidification nitrite. When the electron-withdrawing nitro group is bonded to alkenyl groups, this confers an electrophilic reactivity to fatty acids (17, 18). Thus, fatty acid nitroalkenes can modify proteins covalently via reversible Michael addition reactions that overall serves to link cellular metabolic and redox homeostasis with the posttranslational regulation of target protein function.Nitro fatty acids, which have been detected endogenously in plasma and urine of humans, animal models, and plants (19–21), mediate salutary cardiovascular signaling actions (22). For example they relax blood vessels, attenuate platelet activation, and reduce inflammation via cyclic guanosine monophosphate (cGMP)-independent mechanisms (23, 24). Of relevance, the Mediterranean diet is characterized by high consumption of unsaturated fatty acids, especially from olive oil and fish rich in oleic and linoleic acid, together with vegetables rich in nitrite and nitrate (25). The acidic and low-oxygen conditions in the stomach provide an environment for efficient nitration of such unsaturated fatty acids by nitrite (26).NO₂-OA normalizes blood pressure in an angiotensin (Ang) II-induced murine model of hypertension via undefined mechanisms (27). This was notable as pharmacological inhibitors of sEH also lower BP in murine hypertension, including salt- or Ang II-induced models (6, 7). As NO₂-OA inhibits sEH, we hypothesized that this mechanism may account for BP lowering in the setting of hypertension. Furthermore, as the Mediterranean diet both contains nitro fatty acids and can elevate their endogenous generation, this mechanism may contribute to dietary-induced BP decreases that in turn will reduce the risk of adverse cardiovascular event (28).Given the complexity of causally establishing whether nitro fatty acids lower BP by inhibiting sEH, especially in the setting of dietary-induced endogenous fatty acid nitration, we generated a Cys521Ser sEH knockin (KI) mouse. This “redox-inactive” sEH thiol mutant, rendered insensitive to adductive inhibition by lipid electrophiles in vitro, provided a novel model system for testing the impact of lipid nitroalkenes on sEH hydrolysis of vasoactive EET species and downstream physiological responses (1). The data reveal that nitro fatty acids, applied exogenously as a pharmacological agent or generated endogenously as part of the Mediterranean diet, inhibit sEH to elevate plasma EETs, which in turn lower BP.     

Cyber bullying in ADHD and Asperger Syndrome populations

Cyber bullying or electronic bullying refers to bullying that occurs through the Internet or cellular phones. With the rise of technology, researchers have shown a keen interest in the topic of cyber bullying. However, that interest has not extended to individuals with special needs. To address this gap in the literature, the current study examined the prevalence of both “traditional” bullying and cyber bullying in youth with ADHD and/or Asperger's Syndrome, and assessed the social, psychological, and health effects of bullying on participants. In addition, the study addressed the disconnect between parents’ understanding of their child's online experiences and their child's actual experiences in the virtual world. Forty-two children and youth reported high rates of bullying victimization through both traditional and electronic means. Individuals not involved with bullying showed greater levels of physical and psychological health relative to those involved with bullying. Parents and children disagreed on a number of issues related to use of the Internet, indicating the need for more clear communication between parents and their children. The results are discussed in terms of theory of mind, both for self and for others.     

Nimesil effectiveness in rheumatoid arthritis

Clinical efficiency and safety of nimesil were studied in the multicenter open clinical trial of 52 patients with verified rheumatoid arthritis. Nimesil was given for 12 weeks in a daily dose 200-400 mg in addition to basic therapy. Clinical and laboratory parameters were assessed after 4 and 8 weeks of the treatment and after its end. The treatment produced a significant positive response of the articular syndrome. Marked improvement was registered in 11 (23.4%) patients, improvement--in 33 (79.2%) patients. Side effects were reversible and occurred in 8 (15.3%) patients. In 5 patients the drug was withdrawn. The conclusion is made on high efficiency and good tolerance of nimesil in rheumatoid arthritis patients.     

In vitro assessment of MR relaxation properties of pituitary adenomas

Proton magnetic relaxation times (T1 and T2) and bound water content were measured in vitro in pituitary adenomas from 15 patients using 90 MHz radiofrequency excitation. These data were compared with those measured in normal pituitary glands obtained from four cats and seven fresh human cadavers. The T1 and T2 measured at 24 degrees C in the tumors (mean +/- SD: 1,170 +/- 80 and 123 +/- 35 ms, respectively) were significantly higher than those of cadaver pituitary (830 +/- 200 and 76 +/- 12 ms) and cat pituitary gland (790 +/- 120 and 69 +/- 10 ms). Although the absolute values were lower, similar differences were present in T1 measured at 4 degrees C. Two-dimensional T2 versus T1 plot was particularly helpful in distinguishing tumor from the normal gland. When tumors were grouped according to density on CT, histology or previous treatment (e.g., irradiation or bromocriptine), there were no significant differences in T1 values between the groups. Bound water content was not found to correlate with T1 or T2 values. We concluded that pituitary adenomas can be distinguished from normal pituitary glands by their different relaxation properties when measured at high frequency in vitro MR.     

SIRT2 directs the replication stress response through CDK9 deacetylation

Sirtuin 2 (SIRT2) is a sirtuin family deacetylase that directs acetylome signaling, protects genome integrity, and is a murine tumor suppressor. We show that SIRT2 directs replication stress responses by regulating the activity of cyclin-dependent kinase 9 (CDK9), a protein required for recovery from replication arrest. SIRT2 deficiency results in replication stress sensitivity, impairment in recovery from replication arrest, spontaneous accumulation of replication protein A to foci and chromatin, and a G2/M checkpoint deficit. SIRT2 interacts with and deacetylates CDK9 at lysine 48 in response to replication stress in a manner that is partially dependent on ataxia telangiectasia and Rad3 related (ATR) but not cyclin T or K, thereby stimulating CDK9 kinase activity and promoting recovery from replication arrest. Moreover, wild-type, but not acetylated CDK9, alleviates the replication stress response impairment of SIRT2 deficiency. Collectively, our results define a function for SIRT2 in regulating checkpoint pathways that respond to replication stress through deacetylation of CDK9, providing insight into how SIRT2 maintains genome integrity and a unique mechanism by which SIRT2 may function, at least in part, as a tumor suppressor protein.