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Ribosomal defects perturb stem cell differentiation, and this is the cause of ribosomopathies. How ribosome levels control stem cell differentiation is not fully known. Here, we discover that three DExD/H-box proteins govern ribosome biogenesis (RiBi) and Drosophila oogenesis. Loss of these DExD/H-box proteins, which we name Aramis, Athos, and Porthos, aberrantly stabilizes p53, arrests the cell cycle, and stalls germline stem cell (GSC) differentiation. Aramis controls cell-cycle progression by regulating translation of mRNAs that contain a terminal oligo pyrimidine (TOP) motif in their 5' UTRs. We find that TOP motifs confer sensitivity to ribosome levels that are mediated by La-related protein (Larp). One such TOP-containing mRNA codes for novel nucleolar protein 1 (Non1), a conserved p53 destabilizing protein. Upon a sufficient ribosome concentration, Non1 is expressed, and it promotes GSC cell-cycle progression via p53 degradation. Thus, a previously unappreciated TOP motif in Drosophila responds to reduced RiBi to co-regulate the translation of ribosomal proteins and a p53 repressor, coupling RiBi to GSC differentiation.

TOR (target of rapamycin), a ubiquitous protein kinase central to cellular homeostasis maintenance, fundamentally regulates ribosome biogenesis in part by its target La-related protein 1 (LARP1). Among other target transcripts, LARP1 specifically binds TOP (terminal oligopyrimidine) mRNAs encoding all 80 ribosomal proteins in a TOR-dependent manner through its C-terminal region containing the DM15 module. Though the functional implications of the LARP1 interaction with target mRNAs is controversial, it is clear that the TOP-LARP1-TOR axis is critical to cellular health in humans. Its existence and role in evolutionarily divergent animals remain less understood. We focused our work on expanding our knowledge of the first arm of the axis: the connection between LARP1-DM15 and the 5' TOP motif. We show that the overall DM15 architecture observed in humans is conserved in fruit fly and zebrafish. Both adopt familiar curved arrangements of HEAT-like repeats that bind 5' TOP mRNAs on the same conserved surface, although molecular dynamics simulations suggest that the N-terminal fold of the fruit fly DM15 is predicted to be unstable and unfold. We demonstrate that each ortholog interacts with TOP sequences with varying affinities. Importantly, we determine that the ability of the DM15 region to bind some TOP sequences but not others might amount to the context of the RNA structure, rather than the ability of the module to recognize some sequences but not others. We propose that TOP mRNAs may retain similar secondary structures to regulate LARP1 DM15 recognition. [ABSTRACT FROM AUTHOR]

Background and objectiveNanotechnology offers the possibility of creating multi-functional structures that can provide solutions for biomedical problems. The nanoprobes herein described are an example of such structures, where nano-scaled particles have been designed to provide high specificity and contrast potential for optical detection of cancer. Specifically, enzymatically activated fluorescent nanoprobes (EANPs) were synthesized as cancer-specific contrast agents for optical imaging.Study design/materials and methodsEANPs were prepared by nanoprecipitation of blends of poly(lactic acid)-b-poly(ethylene glycol) and poly(lactic-co-glycolic acid)-b-poly(l-lysine). The lysine moieties were then covalently decorated with the near infrared (NIR) fluorescent molecule AlexaFluor-750 (AF750). Close proximity of the fluorescent molecules to each other resulted in fluorescence quenching, which was reversed by enzymatically mediated cleavage of poly(l-lysine) chains. EANPs were characterized by dynamic light scattering and electron microscopy. Enzymatic development of fluorescence was studied in vitro by fluorescence spectroscopy. Biocompatibility and contrast potential of EANPs were studied in cancerous and noncancerous cells. The potential of the nanoprobes as contrast agents for NIR fluorescence imaging was studied in tissue phantoms.ResultsSpherical EANPs of ∼100 nm were synthesized via nanoprecipitation of polymer blends. Fluorescence activation of EANPs by treatment with a model protease was demonstrated with up to 15-fold optical signal enhancement within 120 minutes. Studies with MDA-MB-231 breast cancer cells demonstrated the cytocompatibility of EANPs, as well as enhanced fluorescence associated with enzymatic activation. Imaging studies in tissue phantoms confirmed the ability of a simple imaging system based on a laser source and CCD camera to image dilute suspensions of the nanoprobe at depths of up to 4 mm, as well as up to a 13-fold signal-to-background ratio for enzymatically activated EANPs compared to un-activated EANPs at the same concentration.ConclusionNanoprecipitation of copolymer blends containing poly(l-lysine) was utilized as a method for preparation of highly functional nanoprobes with high potential as contrast agents for fluorescence based imaging of cancer. Lasers Surg. Med. 47:579-594, 2015. © 2015 Wiley Periodicals, Inc.

The impact of the coronavirus disease‐2019 (COVID‐19) pandemic has been felt worldwide. While the United States appears to be on path to recovery, the economic burden and rising medical care expenditures associated with the pandemic remains in the trillions of dollars. Utilizing data from the US Department of Health and Human Services and FAIR Health, this study estimates the economic burden of COVID‐19 for Idaho was estimated through assessment of direct medical costs and indirect costs for years 2020–2021. Total direct medical hospital costs associated with COVID‐19, among adults, were estimated as the sum of hospital costs associated with inpatient visits. The cost of testing was included in the direct cost assessment, with data from the Idaho Division of Public Health and Medicare Administrative Contractor payment rates. To determine indirect absenteeism costs, daily cases were multiplied by 7 to account for days of missed productivity; this number was then multiplied by an employment‐adjusted average daily wage to obtain a lost productivity dollar value. Lastly, premature mortality costs were estimated based on the lost value of future earnings. Results show that in 2020, the associated direct and indirect costs of COVID‐19 amounted to over $608 million and increased to over $1.3 billion in 2021 for the state of Idaho. As the pandemic lingers on with new variants and mutations, rising costs will continue to place a heavy burden on many Idahoans, who are already often face disparate health outcomes and access to health care. Key points: The economic burden of the COVID‐19 pandemic is in the trillions of dollars.Idaho is a uniquely rural and western state with low vaccination rates.In Idaho, direct and indirect costs of the COVID‐19 pandemic were high.Idaho's total economic burden exceeded $601 million in 2020 and $1.35 billion in 2021. [ABSTRACT FROM AUTHOR]

The incidence of Alzheimer’s disease increases in people who have had an ischemic episode. Furthermore, APP expression is increased following ischemic or hypoxic conditions, as is the production of the Aβ peptide. To address the question of why APP and Aβ are increased in hypoxic and ischemic conditions we induced an ischemic episode in APP knockout mice (APP−/−) and BACE1 knockout mice (BACE−/−). We find that both APP−/− and BACE−/− mice have a dramatically increased risk of mortality as a result of cerebral ischemia. Furthermore, APP knockout mice have reduced cerebral blood flow in response to hypoxia, while wild-type mice maintain or increase cerebral blood flow to the same conditions. The transcription factor, serum response factor (SRF), and calcium-binding molecule, calsequestrin, both involved in vascular regulation, are significantly altered in the brains of APP−/− mice compared to wild type controls. These results show that APP regulates cerebral blood flow in response to hypoxia, and that it, and its cleavage fragments, are crucial for rapid adaptation to ischemic conditions.

We report the use of spectral Doppler optical coherence tomography imaging (SDOCTI) for quantitative evaluation of dynamic blood circulation before and after a localized ischemic stroke in a mouse model. Rose Bengal photodynamic therapy (PDT) is used as a noninvasive means for inducing localized ischemia in cortical microvasculature of the mouse. Fast, repeated Doppler optical coherence tomography scans across vessels of interest are performed to record flow dynamic information with high temporal resolution. Doppler-angle-independent flow indices are used to quantify vascular conditions before and after the induced ischemia by the photocoagulation of PDT. The higher (or lower) flow resistive indices are associated with higher (or lower) resistance states that are confirmed by laser speckle flow index maps (of laser speckle imaging). Our in vivo experiments shows that SDOCTI can provide complementary quantified flow information that is an alternative to blood volume measurement, and can be used as a means for cortical microvasculature imaging well suited for small animal studies.

We present a combined optical Doppler tomography/spectral Doppler imaging modality to quantitatively evaluate the dynamic blood circulation and the artery blockage before and after a localized ischemic stroke in a mouse model. Optical Doppler Tomography (ODT) combines the Doppler principle with optical coherence tomography for noninvasive localization and measurement of particle flow velocity in highly scattering media with micrometer scale spatial resolution. Spectral Doppler imaging (SDI) provides complementary temporal flow information to the spatially distributed flow information of Doppler imaging. Fast, repeated, ODT scans across an entire vessel were performed to record flow dynamic information with high temporal resolution of cardiac cycles. Spectral Doppler analysis of continuous Doppler images demonstrates how the velocity components and longitudinally projected flow-volume-rate change over time for scatters within the imaging volume using spectral Doppler waveforms. Furthermore, vascular conditions can be quantified with various Doppler-angle-independent flow indices. Non-invasive in-vivo mice experiments were performed to evaluate microvascular blood circulation of a localized ischemic stroke mouse model. © 2010 Copyright SPIE - The International Society for Optical Engineering.

The purpose of this paper is to describe the implementation and outcomes of a unique traumatic brain injury (TBI) screening initiative serving the community, with a focus on underserved populations. Idaho's definition of underserved populations includes people living in rural/frontier areas, people experiencing homelessness or intimate partner violence, people with co-occurring disorders, and people with cultural and/or linguistically diverse backgrounds. The goals of screenings are to help participants gain awareness about the likelihood of having experienced a TBI, bridge the gap in TBI reporting, and provide needed support to underserved populations in a rural state. Our work represents a cross-sectional study. Beginning in 2014, TBI screenings were conducted by the Institute of Rural Health within a public health university with several internal and external partners, as well as grant funding for work. Trained interprofessional health students and/or members of the Institute of Rural Health performed TBI screenings using the Ohio State University TBI Identification Method—Interview Form. Those who screened as likely experiencing a TBI received resources for care and follow-up telephone calls. Data were collected on the number of individuals screened and their results and reported using descriptive statistics. From 2014 to 2022, a total of 1333 individuals were screened at 23 different community events across Idaho. Over 30% of screened individuals reported a history of head or neck injury, primarily due to falls and being hit by objects. The majority of identified cases of TBI were characterized by no loss of consciousness or <30 min of unconsciousness. Screenings targeting underserved populations showed higher TBI prevalence. Targeting underserved populations proved valuable in identifying TBI cases. The collaborative and interprofessional approach of this screening is unique and highlights the potential to address complex health issues effectively. These findings offer valuable insights for others implementing TBI screening programs in community settings. [ABSTRACT FROM AUTHOR]

Background: In April 2020, pharmacists were added as medical providers under Idaho Medicaid in response to recent scope expansion for pharmacists and to increase beneficiaries' access to coronavirus disease 2019 (COVID-19) testing and services. The COVID-19 pandemic prompted expedited Medicaid enrollment for pharmacists but did not address coverage of medical services provided to privately insured individuals for pharmacy-based testing services. Objective: This study aimed to describe processes used by independently owned, community-based pharmacies in Idaho to credential with private insurers and report outcomes. Methods: Relevant information and forms required to credential with the four major payers in the state of Idaho were collected. Packets were obtained via medical insurers' websites and by direct contact. Questions that arose from community pharmacists during the submission process were collected and answered on a shared spreadsheet, and insurance representatives were contacted directly to resolve questions. Results: Eight out of 13 participating pharmacies submitted an average of three credentialing packets for their facilities. Thirty-five pharmacists also submitted an average of four credentialing packets for themselves. As of mid-May 2021, nearly 20 weeks after submission, only 67 out of 129 pharmacists had received word regarding the status of their applications. Less than half of all pharmacist applications were approved (after their first attempt). Conclusion: Efforts to support the education of both pharmacists and medical insurers may streamline the credentialing processes in the future. [ABSTRACT FROM AUTHOR]