While many regulators of axon regeneration have been identified, very little is known about mechanisms that allow dendrites to regenerate after injury. Using a Drosophila model of dendrite ...regeneration, we performed a candidate screen of receptor tyrosine kinases (RTKs) and found a requirement for RTK-like orphan receptor (Ror). We confirmed that Ror was required for regeneration in two different neuron types using RNA interference (RNAi) and mutants. Ror was not required for axon regeneration or normal dendrite development, suggesting a specific role in dendrite regeneration. Ror can act as a Wnt coreceptor with frizzleds (fzs) in other contexts, so we tested the involvement of Wnt signaling proteins in dendrite regeneration. We found that knockdown of fz, dishevelled (dsh), Axin, and gilgamesh (gish) also reduced dendrite regeneration. Moreover, Ror was required to position dsh and Axin in dendrites. We recently found that Wnt signaling proteins, including dsh and Axin, localize microtubule nucleation machinery in dendrites. We therefore hypothesized that Ror may act by regulating microtubule nucleation at baseline and during dendrite regeneration. Consistent with this hypothesis, localization of the core nucleation protein γTubulin was reduced in Ror RNAi neurons, and this effect was strongest during dendrite regeneration. In addition, dendrite regeneration was sensitive to partial reduction of γTubulin. We conclude that Ror promotes dendrite regeneration as part of a Wnt signaling pathway that regulates dendritic microtubule nucleation.
Kinetochores are quintessential mitotic structures that monitor microtubule connections to chromosomes. Here, it is shown that kinetochore proteins are required in mature neurons for normal ...regeneration of injured dendrites. At the subcellular level they control microtubule nucleation, specifically in dendrites.
Kinetochores connect centromeric chromatin to spindle microtubules during mitosis. Neurons are postmitotic, so it was surprising to identify transcripts of structural kinetochore (KT) proteins and regulatory chromosome passenger complex (CPC) and spindle assembly checkpoint (SAC) proteins in Drosophila neurons after dendrite injury. To test whether these proteins function during dendrite regeneration, postmitotic RNA interference (RNAi) was performed and dendrites or axons were removed using laser microsurgery. Reduction of KT, CPC, and SAC proteins decreased dendrite regeneration without affecting axon regeneration. To understand whether neuronal functions of these proteins rely on microtubules, we analyzed microtubule behavior in uninjured neurons. The number of growing plus, but not minus, ends increased in dendrites with reduced KT, CPC, and SAC proteins, while axonal microtubules were unaffected. Increased dendritic microtubule dynamics was independent of dual leucine zipper kinase (DLK)-mediated stress but was rescued by concurrent reduction of γ-tubulin, the core microtubule nucleation protein. Reduction of γ-tubulin also rescued dendrite regeneration in backgrounds containing kinetochore RNAi transgenes. We conclude that kinetochore proteins function postmitotically in neurons to suppress dendritic microtubule dynamics by inhibiting nucleation.
Background: African-Americans have twice the risk of non-Hispanic whites for presenting with advanced-stage prostate cancer. To investigate the reasons for this difference, we evaluated the ...association between race/ethnicity and advanced-stage prostate cancer, adjusting for demographic, socioeconomic, clinical, and pathologic factors. Methods: A population-based cohort of 3173 men diagnosed with prostate cancer between October 1, 1994, and October 31, 1995, was analyzed. Medical record abstracts and self-administered survey questionnaires were used to obain information regarding race/ethnicity, age, marital status, insurance status, educational level, household income, employment status, comorbidity, urinary function, prostate-specific antigen level, tumor grade, and clinical stage. The odds ratio (OR) for advanced-stage prostate cancer was estimated with weighted logistic regression analysis. All P values were two-sided. Results: Clinically advanced-stage prostate cancers were detected more frequently in African-Americans (12.3%) and Hispanics (10.5%) than in non-Hispanic whites (6.3%). Socioeconomic, clinical, and pathologic factors each accounted for about 15% of the increased relative risk. After adjusting for all covariates, the risk remained statistically significantly increased for African-Americans (OR = 2.26; 95% confidence interval CI = 1.43 to 3.58) but not for Hispanics (OR = 1.23; 95% CI = 0.73 to 2.08). Conclusion: Traditional socioeconomic, clinical, and pathologic factors accounted for the increased relative risk for presenting with advanced-stage prostate cancer in Hispanic but not in African-American men.
A realistic numerical model is used to study the circulation and mixing of the Salish Sea, a large, complex estuarine system on the United States and Canadian west coast. The Salish Sea is ...biologically productive and supports many important fisheries but is threatened by recurrent hypoxia and ocean acidification, so a clear understanding of its circulation patterns and residence times is of value. The estuarine exchange flow is quantified at 39 sections over 3 years (2017–2019) using the Total Exchange Flow method. Vertical mixing in the 37 segments between sections is quantified as opposing vertical transports: the efflux and reflux. Efflux refers to the rate at which deep, landward‐flowing water is mixed up to become part of the shallow, seaward‐flowing layer. Similarly, reflux refers to the rate at which upper layer water is mixed down to form part of the landward inflow. These horizontal and vertical transports are used to create a box model to explore residence times in a number of different sub‐volumes, seasons, and years. Residence times from the box model are generally found to be longer than those based on simpler calculations of flushing time. The longer residence times are partly due to reflux, and partly due to incomplete tracer homogenization in sub‐volumes. The methods presented here are broadly applicable to other estuaries.
Plain Language Summary
The Salish Sea is a large estuarine system that includes the cities of Vancouver on the Strait of Georgia and Seattle on Puget Sound. Despite the many rivers flowing into the Salish Sea, the water in the system is mostly ocean water, and there is rapid exchange with the ocean. This exchange is important because it brings in most of the nutrients that feed the ecosystem, and it flushes the system relatively rapidly, leading to generally good water quality. Nonetheless, there are places and times in the Salish Sea that experience problems like hypoxia and fish kills. The goal of this work is to clearly describe the patterns of circulation and mixing throughout the Salish Sea so that we may understand the causes and potential future changes in these water quality problems. We use a realistic computer simulation, tested against many observations, to predict the circulation and mixing patterns. We then use those currents to estimate residence times in different parts of the Salish Sea for different seasons and years. The most important result is that we find that the mixing of surface water with deep water can distribute water properties throughout the Salish Sea, increasing the residence time.
Key Points
The estuarine circulation throughout the Salish Sea is estimated over 3 years from a realistic numerical model, focusing on the exchange flow
The vertical mixing, or “reflux” is stronger at sills, but is also large when integrated over the basins between sills
Residence time is calculated in three ways, quantifying the extent to which it is increased (often more than doubled) by reflux and incomplete homogenization within a volume
The use of inhaled, fixed-dose, long-acting muscarinic antagonists (LAMA) combined with long-acting, beta
-adrenergic receptor agonists (LABA) has become a mainstay in the maintenance treatment of ...chronic obstructive pulmonary disease (COPD). One of the fixed-dose LAMA/LABA combinations is the dry powder inhaler (DPI) of umeclidinium bromide (UMEC) and vilanterol trifenatate (VI) (62.5 µg/25 µg) approved for once-a-day maintenance treatment of COPD. This paper reviews the use of fixed-dose combination LAMA/LABA agents focusing on the UMEC/VI DPI inhaler in the maintenance treatment of COPD. The fixed-dose combination LAMA/LABA inhaler offers a step beyond a single inhaled maintenance agent but is still a single device for the COPD patient having frequent COPD exacerbations and persistent symptoms not well controlled on one agent. Currently available clinical trials suggest that the once-a-day DPI of UMEC/VI is well-tolerated, safe and non-inferior or better than other currently available inhaled fixed-dose LAMA/LABA combinations for COPD.
Diet plasticity is a common behavior exhibited by piscivores to sustain predator biomass when preferred prey biomass is reduced. Invasive piscivore diet plasticity could complicate suppression ...success; thus, understanding invasive predator consumption is insightful to meeting conservation targets. Here, we determine if diet plasticity exists in an invasive apex piscivore and whether plasticity could influence native species recovery benchmarks and invasive species suppression goals. We compared diet and stable isotope signatures of invasive lake trout and native Yellowstone cutthroat trout (cutthroat trout) from Yellowstone Lake, Wyoming, U.S.A. as a function of no, low-, moderate-, and high-lake trout density states. Lake trout exhibited plasticity in relation to their density; consumption of cutthroat trout decreased 5-fold (diet proportion from 0.89 to 0.18) from low- to high-density state. During the high-density state, lake trout switched to amphipods, which were also consumed by cutthroat trout, resulting in high diet overlap (Schoener's index value, D = 0.68) between the species. As suppression reduced lake trout densities (moderate-density state), more cutthroat trout were consumed (proportion of cutthroat trout = 0.42), and diet overlap was released between the species (D = 0.30). A shift in lake trout δ13C signatures from the high- to the moderate-density state also corroborated increased consumption of cutthroat trout and lake trout diet plasticity. Observed declines in lake trout are not commensurate with expected cutthroat trout recovery due to lake trout diet plasticity. The abundance of the native species in need of conservation may take longer to recover due to the diet plasticity of the invasive species. The changes observed in diet, diet overlap, and isotopes associated with predator suppression provides more insight into conservation and suppression dynamics than using predator and prey biomass alone. By understanding these dynamics, we can better prepare conservation programs for potential feedbacks caused by invasive species suppression.
Background:
Recurrent intake of 4 g/day or more of acetaminophen has been associated with elevation of serum alanine aminotransferase (ALT) levels in 30–40% of the exposed population and may result ...in hepatotoxicity.
Objective:
To describe the frequency that patients are prescribed acetaminophen doses that exceed 4 g/day across a large population.
Methods:
Using California's Medicaid (MediCal) fee-for-service population, pharmacy claims including over-the-counter (OTC) medications were examined for prescriptions that could result in acetaminophen doses of 4 g/day or more. The period studied, October 2004 through September 2005, was before the Part D pharmacy benefit was available to dually eligible Medicare patients when all prescriptions were covered by the MediCal claims process.
Results:
During the pre-Part D evaluation period, approximately 3.27 million beneficiaries were enrolled in the fee-for-service MediCal program. A total of 192,716 (5.9%) were potentially exposed to at least 1 day of 4 g/day or more of acetaminophen. Of those, 769 patients were potentially exposed to at least 1 day of 16 g/day or more. A total of 2664 beneficiaries were dispensed prescriptions and OTC products that, if taken as directed, would have resulted in more than 100 days of acetaminophen doses of 4 g/day or more during the study year.
Conclusions:
Despite electronic systems designed to warn dispensing pharmacists of duplications of drug class and cumulative excessive doses, potentially toxic amounts of acetaminophen are commonly prescribed and dispensed to this population. Better systems, increased awareness, and education of patients, prescribers, and pharmacists are needed to reduce this potential toxic exposure.
An abstract of a study by Serrano et al determining from non-caregiver stakeholders in the child welfare system about their perspectives on what barriers prevent effective discussions about sexual ...health between caregivers and foster youth, strategies they have observed to be effective in facilitating these conversations, and recommendations to better inform the development of effective trainings and STI and pregnancy prevention efforts is presented. Child welfare stakeholders identified several barriers and facilitators to sexual heath discussions between foster/kinship caregivers and youth. This input provides an upstream perspective which can be used to design more effective trainings as well as other types of multilevel interventions to improve reproductive health outcomes among foster youth.
PDF
