NR4A Gene Expression Is Dynamically Regulated in the Ventral Tegmental Area Dopamine Neurons and Is Related to Expression of Dopamine Neurotransmission Genes

The NR4A transcription factors NR4A1, NR4A2, and NR4A3 (also known as Nur77, Nurr1, and Nor1, respectively) share similar DNA-binding properties and have been implicated in regulation of dopamine neurotransmission genes. Our current hypothesis is that NR4A gene expression is regulated by dopamine neuron activity and that induction of NR4A genes will increase expression of dopamine neurotransmission genes. Eticlopride and γ-butyrolactone (GBL) were used in wild-type (+/+) and Nurr1-null heterozygous (+/−) mice to determine the mechanism(s) regulating Nur77 and Nurr1 expression. Laser capture microdissection and real-time PCR was used to measure Nurr1 and Nur77 mRNA levels in the ventral tegmental area (VTA). Nur77 expression was significantly elevated 1 h after both GBL (twofold) and eticlopride (fourfold). In contrast, GBL significantly decreased Nurr1 expression in both genotypes, while eticlopride significantly increased Nurr1 expression only in the +/+ mice. In a separate group of mice, haloperidol injection significantly elevated Nur77 and Nor1, but not Nurr1 mRNA in the VTA within 1 h and significantly increased tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA expression by 4 h. These data demonstrate that the NR4A genes are dynamically regulated in dopamine neurons with maintenance of Nurr1 expression requiring dopamine neuron activity while both attenuation of dopamine autoreceptors activation and dopamine neuronal activity combining to induce Nur77 expression. Additionally, these data suggest that induction of NR4A genes could regulate TH and DAT expression and ultimately regulate dopamine neurotransmission

Utilization of Vertebroplasty/Kyphoplasty in the Management of Compression Fractures: National Trends and Predictors of Vertebroplasty/Kyphoplasty

Objective The purpose of this study is to examine the utilization of kyphoplasty/vertebroplasty procedures in the management of compression fractures. With the growing elderly population and the associated increase in rates of osteoporosis, vertebral compression fractures have become a daily encounter for spine surgeons. However, there remains a lack of consensus on the optimal management of this patient population. Methods A retrospective analysis of 91 million longitudinally followed patients from 2016 to 2019 was performed using the PearlDiver Patient Claims Database. Patients with compression fractures were identified using International Classification of Disease, 10th Revision codes, and a subset of patients who received kyphoplasty/vertebroplasty were identified using Common Procedural Terminology codes. Baseline demographic and clinical data between groups were acquired. Multivariable regression analysis was performed to determine predictors of receiving kyphoplasty/vertebroplasty. Results A total of 348,457 patients with compression fractures were identified with 9.2% of patients receiving kyphoplasty/vertebroplasty as their initial treatment. Of these patients, 43.5% underwent additional kyphoplasty/vertebroplasty 30 days after initial intervention. Patients receiving kyphoplasty/vertebroplasty were significantly older (72.2 vs. 67.9, p < 0.05), female, obese, had active smoking status and had higher Elixhauser Comorbidity Index scores. Multivariable analysis demonstrated that female sex, smoking status, and obesity were the 3 strongest predictors of receiving kyphoplasty/vertebroplasty (odds ratio, 1.27, 1.24, and 1.14, respectively). The annual rate of kyphoplasty/vertebroplasty did not change significantly (range, 8%–11%). Conclusion The majority of vertebral compression fractures are managed nonoperatively. However, certain patient factors such as smoking status, obesity, female sex, older age, osteoporosis, and greater comorbidities are predictors of undergoing kyphoplasty/vertebroplasty

Does diet affect breast cancer risk?

The role of specific dietary factors in breast cancer causation is not completely resolved. Results from prospective studies do not support the concept that fat intake in middle life has a major relation to breast cancer risk. However, weight gain in middle life contributes substantially to breast cancer risk. Alcohol is the best established dietary risk factor, probably by increasing endogenous estrogen levels. Hypotheses relating diet during youth to risk decades later will be difficult to test. Nevertheless, available evidence is strong that breast cancer risk can be reduced by avoiding weight gain during adult years, and by limiting alcohol consumption

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Multi-threshold CMOS Circuit Design Methodology from 2D to 3D

A new and exciting approach in digital IC design in order to accommodate the Moore\u27s law is 3D chip stacking. Chip stacking offers more transistors per chip, reduced wire lengths, and increased memory access bandwidths. This thesis demonstrates that traditional 2D design flow can be adapted for 3D chip stacking. 3D chip stacking has a serious drawback: heat generation. Die-on-die architecture reduces exposed surface area for heat dissipation. In order to reduce heat generation, a low power technique named Multi-Threshold CMOS (MTCMOS) was incorporated in this work. MTCMOS required designing a power management unit (to control when and which gates are powered), a MTCMOS gate library, and a state saving D-Flip-Flop. This thesis demonstrates converting a traditional 2D chip to a low heat 3D chip design with the use of MTCMOS technology using industry-standard CAD tools

Expression of Murine APOBEC3 Alleles in Different Mouse Strains and Their Effect on Mouse Mammary Tumor Virus Infection▿ †

Recent work has shown that mouse APOBEC3 restricts infection by mouse mammary tumor virus (MMTV) and murine leukemia virus (MLV) and that there are polymorphic APOBEC3 alleles found in different inbred mouse strains. For example, C57BL/6 mice, which are resistant to Friend MLV (F-MLV), encode a APOBEC3 gene different from that encoded by F-MLV-susceptible BALB/c mice; the predominant RNA produced in C57BL/6 mice lacks exon 5 (mA3−5) and encodes a protein with 15 polymorphic amino acids. It has also been reported that BALB/c mice produce only a variant RNA that lacks exon 2 (mA3−2). In this study, we examined the effect of these polymorphic APOBEC3 proteins on MMTV infection. We found that the major RNA made in C57BL/6 and B10.BR mice lacks exon 5 but that BALB/c and C3H/HeN mice predominantly express an RNA that contains all nine exons. In addition to producing the splice variant, C57BL/6 and B10.BR cells and tissues had levels of mA3 RNA fivefold higher than those from BALB/c and C3H/HeN mice. A cloned C57BL/6-derived mA3 protein lacking exon 5 inhibited MMTV infection better than a cloned full-length protein derived from 129/Ola RNA when packaged into MMTV virions. We also tested dendritic cells derived from different inbred mouse strains for their abilities to be infected by MMTV and showed that susceptibility to infection correlated with the presence of the exon 5-encoding allele. In vivo susceptibility to infection cosegregated with the inherited mA3 allele in a C57BL/6 × BALB/c backcross analysis. Moreover, virus produced in vivo in the mammary tissue of mA3 knockout and BALB/c mice was more infectious than that produced in the tissue of C57BL/6 mice. These data indicate that mA3 plays a role in the genetics of susceptibility and resistance to MMTV infection

Investigation of supersonic flow over an axisymmetric protuberance

The behavior of a supersonic fluid flow field over an axisymmetric cylindrical body has been simulated using ANSYS Fluent computational fluid dynamics software. The simulated body was altered for successive simulations to incorporate a protuberance interrupting the one dimensional flow along the surface. The effect of introducing this protuberance was investigated for Mach numbers ranging from 1.5 to 5.5 in increments of 0.5. To account for flow characteristics not associated with an infinite wall simulation, the body was modeled as a 2.5 caliber Tangent Ogive nose cone profile leading a cylindrical wall in free stream conditions. Once the initial shock is formed, the flow downstream is investigated for the behavior it exhibits in the presence of a surface protuberance. The surface protuberance will cause the flow to wrap around the curvature of the surface. This abrupt change in direction and redirection results in a separation in the flow structure from the wall, which creates a region known as a recirculation zone. Flow becomes discontinuous due to the turning angle of the surface and therefore detaches and must resume parallel flow farther past the protuberance. Flow reattachment downstream of such an obstacle is determined in this research in order to develop a relationship between flow speed, protuberance geometry and recirculation region length. Pressure distributions along the surface beyond the separation point caused by the protuberance angle were used to find the reattachment length. Each pressure distribution contained a point where the rate of change leveled off from the initial chaotic region following the protuberance apex. These points were considered the beginning of the reattachment region and thus the end of the separation region. Correlations for such behavior as a function of the protuberance length scale and Mach number are developed and discussed. The dominance of the Mach number influence in the reattachment length of the separation region is apparent in the final data analysis, as well as a negative correlation of increasing protuberance height. It is apparent that an increased Mach number results in a longer reattachment length. However, as the aspect ratio of the protuberance increases, the reattachment length decreases. (Published By University of Alabama Libraries

A critically endangered new species of polymorphic stream frog (Anura: Hylidae: Atlantihyla) from the montane rainforest of Refugio de Vida Silvestre Texiguat, Honduras

The Chortís Highlands of Mesoamerica exhibit a high degree of in situ evolutionary diversification, exemplified by numerous endemic radiations of stream-dwelling treefrogs (Anura: Hylidae: Atlantihyla, Duellmanohyla, and Ptychohyla), which have been a source of ongoing taxonomic uncertainty. Recent evidence suggests that one species, Atlantihyla spinipollex, may conceal an unrecognized sister species found in Refugio de Vida Silvestre Texiguat. We applied an iterative integrative taxonomic framework to assess this population within the context of Chortís Highlands populations of Atlantihyla spinipollex sensu stricto, Duellmanohyla salvadorensis, D .  salvavida, D .  soralia, and Ptychohyla hypomykter, using both a single locus (mtDNA: 16S) and multilocus (mtDNA: 12S, 16S; nDNA: POMC, RAG-1, Rhodopsin) datasets accompanied by distance- and tree-based species delimitation methods to inform our taxonomy. Samples of A .  spinipollex sensu lato formed two deeply divergent monophyletic lineages, suggesting that populations from the central and eastern Cordillera Nombre de Dios are conspecific, while the population from Refugio de Vida Silvestre Texiguat represents a previously undescribed species. We analyzed morphological and bioacoustic variation within and between the two lineages of A .  spinipollex sensu lato and found support for recognition of two distinct taxa. We restricted the name A .  spinipollex to populations in the central and eastern Cordillera Nombre de Dios, and formally describe the Texiguat population as a new species. We recommend the new species be considered Critically Endangered due to ongoing habitat loss within what remains of its highly restricted natural distribution. This new species joins 26 other endemic species of amphibians and reptiles at Texigua