Reconsidering the Prohibition against General Solicitation during Section 3(c)(7) Offerings

This paper examines the seventy year history of the general solicitation prohibition during private offerings and then analyzes its continuing relevance as applied to Section 3(c)(7) offerings. The S.E.C. Staff recently issued a report questioning the continuing value of prohibiting general solicitation during private offerings made pursuant to Section 3(c)(7) of the Investment Company Act. If the S.E.C. were to follow the recommendation in the S.E.C. Staff Report, this would have tremendous implications for a growing number of hedge funds, and other investment companies utilizing the Section 3(c)(7) exemption. By allowing general solicitation, the S.E.C. would be reversing a policy with over seventy years of history in order to increase issuers’ access to capital. These potential efficiency gains could come at a cost, however, since many fear that repealing the prohibition against general solicitation will eliminate one more protection for individual investors from risky investment opportunities

Molecular signatures of natural selection for polymorphic genes of the human dopaminergic and serotonergic systems: A review

A large body of research has examined the behavioral and mental health consequences of polymorphisms in genes of the dopaminergic and serotonergic systems. Along with this, there has been considerable interest in the possibility that these polymorphisms have developed and/or been maintained due to the action of natural selection. Episodes of natural selection on a gene are expected to leave molecular “footprints” in the DNA sequences of the gene and adjacent genomic regions. Here we review the research literature investigating molecular signals of selection for genes of the dopaminergic and serotonergic systems. The gene SLC6A4, which codes for a serotonin transport protein, was the one gene for which there was consistent support from multiple studies for a selective episode. Positive selection on SLC6A4 appears to have been initiated ∼ 20–25,000 years ago in east Asia and possibly in Europe. There are scattered reports of molecular signals of selection for other neurotransmitter genes, but these have generally failed at replication across studies. In spite of speculation in the literature about selection on these genes, current evidence from population genomic analyses supports selectively neutral processes, such as genetic drift and population dynamics, as the principal drivers of recent evolution in dopaminergic and serotonergic genes other than SLC6A4

O-linked beta N-acetylglucosamine (O-GlcNAc) post-translational modifications govern axon regeneration

Axonal regeneration within the mammalian central nervous system following traumatic damage is limited and interventions to enable regrowth is a crucial goal in regenerative medicine. The nematode Caenorhabditis elegans is an excellent model to identify the intrinsic genetic programs that govern axonal regrowth. Here we demonstrate that alterations in O-linked N- beta-acetylglucosamine (O-GlcNAc) post-translational modifications of proteins can increase the regenerative potential of individual neurons. O-GlcNAc are single monosaccharide protein modifications that occur on serines/threonines in nucleocytoplasmic compartments. Changes in O-GlcNAc levels serve as a sensor of cellular nutrients and acts in part through the insulin-signaling pathway. Loss of O-GlcNAc via mutation of the O-GlcNAc Transferase (OGT), the enzyme that adds O-GlcNAc onto target proteins, enhances regeneration by 70%. Remarkably, hyper-O-GlcNAcyation via mutation of the O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc from target proteins, also enhances regeneration by 40%. Our results shed light on this apparent contradiction by demonstrating that O-GlcNAc enzyme mutants differentially modulate the insulin-signaling pathway. OGT mutants act through AKT1 to modulate glycolysis. In contrast, OGA mutants act through the FOXO/DAF-16 transcription factor to improve the mitochondrial stress response. These findings reveal for the first time the importance of O-GlcNAc post-translational modifications in axon regeneration and provide evidence that regulation of metabolic programs can dictate the regenerative capacity of a neuron.2021-02-20T00:00:00

Biometal muscle to restore atrial transport function in a permanent atrial fibrillation animal model: a potential tool in the treatment of end-stage heart failure

Background: Half of the patients with end-stage heart failure suffer from persistent atrial fibrillation (AF). Atrial kick (AK) accounts for 10-15% of the ejection fraction. A device restoring AK should significantly improve cardiac output (CO) and possibly delay ventricular assist device (VAD) implantation. This study has been designed to assess the mechanical effects of a motorless pump on the right chambers of the heart in an animal model. Methods: Atripump is a dome-shaped biometal actuator electrically driven by a pacemaker-like control unit. In eight sheep, the device was sutured onto the right atrium (RA). AF was simulated with rapid atrial pacing. RA ejection fraction (EF) was assessed with intracardiac ultrasound (ICUS) in baseline, AF and assisted-AF status. In two animals, the pump was left in place for 4 weeks and then explanted. Histology examination was carried out. The mean values for single measurement per animal with ±SD were analysed. Results: The contraction rate of the device was 60 per min. RA EF was 41% in baseline, 7% in AF and 21% in assisted-AF conditions. CO was 7±0.5lmin−1 in baseline, 6.2±0.5lmin−1 in AF and 6.7±0.5lmin−1 in assisted-AF status (p≪0.01). Histology of the atrium in the chronic group showed chronic tissue inflammation and no sign of tissue necrosis. Conclusions: The artificial muscle restores the AK and improves CO. In patients with end-stage cardiac failure and permanent AF, if implanted on both sides, it would improve CO and possibly delay or even avoid complex surgical treatment such as VAD implantatio

Temporal Changes in Cortical and Hippocampal Expression of Genes Important for Brain Glucose Metabolism Following Controlled Cortical Impact Injury in Mice

Traumatic brain injury (TBI) causes transient increases and subsequent decreases in brain glucose utilization. The underlying molecular pathways are orchestrated processes and poorly understood. In the current study, we determined temporal changes in cortical and hippocampal expression of genes important for brain glucose/lactate metabolism and the effect of a known neuroprotective drug telmisartan on the expression of these genes after experimental TBI. Adult male C57BL/6J mice (n = 6/group) underwent sham or unilateral controlled cortical impact (CCI) injury. Their ipsilateral and contralateral cortex and hippocampus were collected 6 h, 1, 3, 7, 14, 21, and 28 days after injury. Expressions of several genes important for brain glucose utilization were determined by qRT-PCR. In results, (1) mRNA levels of three key enzymes in glucose metabolism [hexo kinase (HK) 1, pyruvate kinase, and pyruvate dehydrogenase (PDH)] were all increased 6 h after injury in the contralateral cortex, followed by decreases at subsequent times in the ipsilateral cortex and hippocampus; (2) capillary glucose transporter Glut-1 mRNA increased, while neuronal glucose transporter Glut-3 mRNA decreased, at various times in the ipsilateral cortex and hippocampus; (3) astrocyte lactate transporter MCT-1 mRNA increased, whereas neuronal lactate transporter MCT-2 mRNA decreased in the ipsilateral cortex and hippocampus; (4) HK2 (an isoform of hexokinase) expression increased at all time points in the ipsilateral cortex and hippocampus. GPR81 (lactate receptor) mRNA increased at various time points in the ipsilateral cortex and hippocampus. These temporal alterations in gene expression corresponded closely to the patterns of impaired brain glucose utilization reported in both TBI patients and experimental TBI rodents. The observed changes in hippocampal gene expression were delayed and prolonged, when compared with those in the cortex. The patterns of alterations were specific to different brain regions and exhibited different recovery periods following TBI. Oral administration of telmisartan (1 mg/kg, for 7 days, n = 10 per group) ameliorated cortical or hippocampal mRNA for Glut-1/3, MCT-1/2 and PDH in CCI mice. These data provide molecular evidence for dynamic alteration of multiple critical factors in brain glucose metabolism post-TBI and can inform further research for treating brain metabolic disorders post-TBI

Exact General Relativistic Perfect Fluid Disks with Halos

Using the well-known ``displace, cut and reflect'' method used to generate disks from given solutions of Einstein field equations, we construct static disks made of perfect fluid based on vacuum Schwarzschild's solution in isotropic coordinates. The same method is applied to different exactsolutions to the Einstein'sequations that represent static spheres of perfect fluids. We construct several models of disks with axially symmetric perfect fluid halos. All disks have some common features: surface energy density and pressures decrease monotonically and rapidly with radius. As the ``cut'' parameter $a$ decreases, the disks become more relativistic, with surface energy density and pressure more concentrated near the center. Also regions of unstable circular orbits are more likely to appear for high relativistic disks. Parameters can be chosen so that the sound velocity in the fluid and the tangential velocity of test particles in circular motion are less then the velocity of light. This tangential velocity first increases with radius and reaches a maximum.Comment: 22 pages, 25 eps.figs, RevTex. Phys. Rev. D to appea

Geranylgeraniol (GGOH), Incorporated into a Bone Cement Pellet Promotes Osteoclast Function and Healing in a Model of Medication-Related Osteonecrosis of the Jaw

INTRODUCTION: There is no cause -based treatment for Medication-Related Osteonecrosis of the Jaw (MRONJ). MRONJ is a morbid condition including exposed, infected bone and mandibular fractures in osteoporotic individuals and metastatic cancers patients treated with nitrogen containing bisphosphonates (NBP). NBPs inhibit farnesyl diphosphate synthase (FDPS) in the mevalonate pathway, depriving osteoclasts and other bone cells of small GTPases necessary for their function and survival. We test the hypothesis that geranylgeraniol (GGOH),a metabolite downstream of FDPS, when incorporated into a bone cement pellet, enhances osteoclast function and promotes local bone healing in METHODS: RESULTS: The release of GGOH from bone cement increased osteoclast survival/metabolic activity, and promoted resorption of the calcified substrate. In vivo released GGOH limited the effects of the bisphosphonate and promoted healing. In an animal pilot study, GGOH from the infused cement carrier stabilizes bone structure and restores the ability of osteoclasts to remodel. CONCLUSION: These initial findings point to GGOH in a bone cement carrier as a useful therapeutic approach to prevent or mitigate the pathogenesis of MRONJ

tofacitinib treatment is associated with modest and reversible increases in serum lipids in patients with ulcerative colitis

Background & Aims Tofacitinib is an oral, small-molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We analyzed inflammation, lipid concentrations, and incidence rates of major adverse cardiovascular (CV) events (MACEs) in patients who received tofacitinib in worldwide studies. Methods We collected data from 1157 patients who participated in 3 8-week induction studies (1 phase-2 study and 2 phase-3 studies; patients received tofacitinib 10 mg twice daily or placebo), a 52-week phase-3 maintenance study of responders (patients received tofacitinib 5 or 10 mg twice daily or placebo), and an ongoing long-term extension study of patients who did and did not respond to induction or maintenance therapy (patients received tofacitinib 5 or 10 mg twice daily). Lipid concentrations were assessed from induction baseline to week 61 (week 52 of maintenance therapy). We calculated MACE incidence rates (patients with ≥1 event per 100 patient-years of exposure) and Reynolds risk score (RRS; a composite score used to determine CV risk) for patients given tofacitinib vs placebo. Results The mean RRS was P Conclusions In an analysis of data from 5 trials of patients with UC who received tofacitinib, we found reversible increases in lipids with treatment and inverse correlations with reduced levels of high-sensitivity C-reactive protein. We did not find clinically meaningful changes in lipid ratios or RRS. MACEs were infrequent and not dose-related. Clinical trial registration Clinicaltrials.gov : A3921063 ( NCT00787202 ); OCTAVE Induction 1 ( NCT01465763 ); OCTAVE Induction 2 ( NCT01458951 ); OCTAVE Sustain ( NCT01458574 ); OCTAVE Open ( NCT01470612

Inferior Olivary nucleus degeneration does not lessen tremor in essential tremor

Background In traditional models of essential tremor, the inferior olivary nucleus was posited to play a central role as the pacemaker for the tremor. However, recent data call this disease model into question. Case presentation Our patient had progressive, long-standing, familial essential tremor. Upper limb tremor began at age 10 and worsened over time. It continued to worsen during the nine-year period he was enrolled in our brain donation program (age 85 – 94 years), during which time the tremor moved from the moderate to severe range on examination. On postmortem examination at age 94, there were degenerative changes in the cerebellar cortex, as have been described in the essential tremor literature. Additionally, there was marked degeneration of the inferior olivary nucleus, which was presumed to be of more recent onset. Such degeneration has not been previously described in essential tremor postmortems. Despite the presence of this degeneration, the patient’s tremor not only persisted but it continued to worsen during the final decade of his life. Conclusions Although the pathophysiology of essential tremor is not completely understood, evidence such as this suggests that the inferior olivary nucleus does not play a critical role in the generation of tremor in these patients