The Dopamine D3 Receptor Antagonist VK4-40 Attenuates Morphine-Induced Hyperactivity But Not Cocaine-Induced Hyperactivity in Mice

In light of the increasing rates of opioid abuse in the US, the search for viable medications to treat opioid abuse disorder (OUD) has become ever more urgent. Opioids exert their abuse-related effects in part by indirectly increasing dopamine (DA) neurotransmission in the mesolimbic system, a dopaminergic projection arising in the ventral tegmental area and terminating in the nucleus accumbens. The DA D3 receptor (D3R), which belongs to the D2 family of dopamine receptors (D2, D3 , D4 receptor subtypes), is highly expressed in these brain regions and has shown strong potential as a pharmacotherapeutic target for the treatment of OUD. More specifically, D3R antagonists have been shown by us and others to attenuate the abuse-related behavioral effects of opioids without producing adverse side effects associated with nonselective D2-like receptor antagonists. We previously examined the effects of the selective D3R antagonist PG01037 (133-fold selectivity for D3R vs. D2R) using drug-induced hyperactivity as a behavioral proxy for DA release within the nucleus accumbens. Interestingly, we found that PG01037 enhances cocaine-induced hyperlocomotion while it attenuates morphine-induced hyperlocomotion in mice. The potentiation of psychostimulant effects could confound the potential use of D3R antagonists for the treatment of OUD, since many opioid users co-abuse stimulants such as cocaine. However, recent studies with more selective D3R antagonists found that they do not enhance certain effects of cocaine while still reducing opioid effects. It is currently unknown what impact these highly-selective D3R antagonists will have on cocaine-induced hyperactivity and/or dopamine neurotransmission. The purpose of this study was to examine the impact of pretreatment with the novel and highly selective D3R antagonist VK4-40 (250-fold selectivity for D3R vs. D2R) on cocaine- and morphine-induced hyperlocomotion in mice

Quantification of rotator cuff tear geometry: the repair ratio as a guide for surgical repair in crescent and U-shaped tears

Surgical repair of symptomatic, retracted rotator cuff tears unresponsive to non-operative treatments requires closure of the tear without undue tension and reattaching the torn tendon to its former insertion site. In this study, the length of the torn tendon edge was hypothesized to be longer than the length of the humeral insertion site. The objective of this study was to quantify the discrepancy in length of the torn tendon edge and the length of the avulsed humeral insertion site. Full thickness, rotator cuff tears that were found in twelve fresh frozen cadaver shoulders was studied. The length of the torn tendon edge, the length of the avulsed humeral insertion site and the retraction were measured using digital calipers. Each tear involved the supraspinatus and the infraspinatus was additionally torn in six. The size of the tear was medium in eight and large in four. The length of the torn tendon edge was always longer than the length of the avulsed humeral insertion site. Retraction was 29.9 ± 9.3 mm (range 21–48 mm). The repair ratio, defined as the ratio of length of torn tendon edge to the length of avulsed humeral insertion site, was 2.6 ± 0.4 (range 2.1–3.5). As only the length of the torn tendon edge equal to the length of the avulsed humeral insertion site can be repaired to bone, a repair ratio more than one precludes a simple repair and an additional repair technique such as margin convergence would be necessary for the remaining unapproximated torn tendon edge in rotator cuff tears. Repair ratio may aid in selection of the surgical repair technique of these rotator cuff tears

The Enzymatic Activity of Type 1 Iodothyronine Deiodinase (D1) is Low in Liver Hemangioma: A Preliminary Study

Type 1 iodothyronine deiodinase (D1) is a crucial enzyme which converts the prohormone thyroxine (T4) into active tri-iodothyronine (T3). There has been strong evidence that the metabolism of thyroid hormones is disturbed in some neoplastic tissues such as thyroid, renal, and breast cancer. However, there are few available data about D1 enzyme activity in benign tumors such as hemangioma, which is the most common primary liver tumor. Hence this study aimed to determine the enzymatic activity of D1 in hemangiomas in relation to healthy liver tissue. Seven tumors and healthy control tissues were obtained from patients who had liver resection due to hemangioma. The activity was assessed by measurement of radioactive iodine released by deiodination catalyzed by D1. It was found that D1 activity was significantly lower in the hemagiomas than in the healthy surrounding tissue (p = 0.0017). The results indicated that thyroid hormones play important roles not only in the regulation of cell metabolism, but also in cell growth, division, and apoptosis. The active form T3 acts through its nuclear receptors and influences the up- and down-regulation of target genes. Healthy liver tissue expresses a high level of D1, but disturbed D1 activity may result in changes in the local concentration of T3 which may impair gene transcription. These finding demonstrate a low enzymatic activity of D1 in liver hemangioma and suggest an as yet unknown role of thyroid hormones in this type of benign liver tumor

The quest for companions to post-common envelope binaries. II. NSVS14256825 and HS0705+6700

We report new mid-eclipse times of the two close binaries NSVS14256825 and HS0705+6700, harboring an sdB primary and a low-mass main-sequence secondary. Both objects display clear variations in the measured orbital period, which can be explained by the action of a third object orbiting the binary. If this interpretation is correct, the third object in NSVS14256825 is a giant planet with a mass of roughly 12 M_Jup. For HS0705+6700, we provide evidence that strengthens the case for the suggested periodic nature of the eclipse time variation and reduces the uncertainties in the parameters of the brown dwarf implied by that model. The derived period is 8.4 yr and the mass is 31 M_Jup, if the orbit is coplanar with the binary. This research is part of the PlanetFinders project, an ongoing collaboration between professional astronomers and student groups at high schools.Comment: Accepted by Astron. and Astrophy

A Complex Containing the CPSF73 Endonuclease and Other Polyadenylation Factors Associates with U7 snRNP and Is Recruited to Histone Pre-mRNA for 3'-End Processing

Animal replication-dependent histone pre-mRNAs are processed at the 3′ end by endonucleolytic cleavage that is not followed by polyadenylation. The cleavage reaction is catalyzed by CPSF73 and depends on the U7 snRNP and its integral component, Lsm11. A critical role is also played by the 220-kDa protein FLASH, which interacts with Lsm11. Here we demonstrate that the N-terminal regions of these two proteins form a platform that tightly interacts with a unique combination of polyadenylation factors: symplekin, CstF64, and all CPSF subunits, including the endonuclease CPSF73. The interaction is inhibited by alterations in each component of the FLASH/Lsm11 complex, including point mutations in FLASH that are detrimental for processing. The same polyadenylation factors are associated with the endogenous U7 snRNP and are recruited in a U7-dependent manner to histone pre-mRNA. Collectively, our studies identify the molecular mechanism that recruits the CPSF73 endonuclease to histone pre-mRNAs, reveal an unexpected complexity of the U7 snRNP, and suggest that in animal cells polyadenylation factors assemble into two alternative complexes—one specifically crafted to generate polyadenylated mRNAs and the other to generate nonpolyadenylated histone mRNAs that end with the stem-loop