Functional loss of a noncanonical BCOR-PRC1.1 complex accelerates SHH-driven medulloblastoma formation.

Medulloblastoma is a malignant childhood brain tumor arising from the developing cerebellum. In Sonic Hedgehog (SHH) subgroup medulloblastoma, aberrant activation of SHH signaling causes increased proliferation of granule neuron progenitors (GNPs), and predisposes these cells to tumorigenesis. A second, cooperating genetic hit is often required to push these hyperplastic cells to malignancy and confer mutation-specific characteristics associated with oncogenic signaling. Somatic loss-of-function mutations of the transcriptional corepressor BCOR are recurrent and enriched in SHH medulloblastoma. To investigate BCOR as a putative tumor suppressor, we used a genetically engineered mouse model to delete exons 9/10 of Bcor (BcorΔE9-10 ) in GNPs during development. This mutation leads to reduced expression of C-terminally truncated BCOR (BCORΔE9-10). While BcorΔE9-10 alone did not promote tumorigenesis or affect GNP differentiation, BcorΔE9-10 combined with loss of the SHH receptor gene Ptch1 resulted in fully penetrant medulloblastomas. In Ptch1+/- ;BcorΔE9-10 tumors, the growth factor gene Igf2 was aberrantly up-regulated, and ectopic Igf2 overexpression was sufficient to drive tumorigenesis in Ptch1+/- GNPs. BCOR directly regulates Igf2, likely through the PRC1.1 complex; the repressive histone mark H2AK119Ub is decreased at the Igf2 promoter in Ptch1+/- ;BcorΔE9-10 tumors. Overall, our data suggests that BCOR-PRC1.1 disruption leads to Igf2 overexpression, which transforms preneoplastic cells to malignant tumors.

Reducing the Antigen Prevalence Target Threshold for Stopping and Restarting Mass Drug Administration for Lymphatic Filariasis Elimination: A Model-Based Cost-effectiveness Simulation in Tanzania, India and Haiti.

BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) aims to reduce and maintain infection levels through mass drug administration (MDA), but there is evidence of ongoing transmission after MDA in areas where Culex mosquitoes are the main transmission vector, suggesting that a more stringent criterion is required for MDA decision making in these settings. METHODS: We use a transmission model to investigate how a lower prevalence threshold (<1% antigenemia [Ag] prevalence compared with <2% Ag prevalence) for MDA decision making would affect the probability of local elimination, health outcomes, the number of MDA rounds, including restarts, and program costs associated with MDA and surveys across different scenarios. To determine the cost-effectiveness of switching to a lower threshold, we simulated 65% and 80% MDA coverage of the total population for different willingness to pay per disability-adjusted life-year averted for India ($446.07), Tanzania ($389.83), and Haiti ($219.84). RESULTS: Our results suggest that with a lower Ag threshold, there is a small proportion of simulations where extra rounds are required to reach the target, but this also reduces the need to restart MDA later in the program. For 80% coverage, the lower threshold is cost-effective across all baseline prevalences for India, Tanzania, and Haiti. For 65% MDA coverage, the lower threshold is not cost-effective due to additional MDA rounds, although it increases the probability of local elimination. Valuing the benefits of elimination to align with the GPELF goals, we find that a willingness to pay per capita government expenditure of approximately $1000-$4000 for 1% increase in the probability of local elimination would be required to make a lower threshold cost-effective. CONCLUSIONS: Lower Ag thresholds for stopping MDAs generally mean a higher probability of local elimination, reducing long-term costs and health impacts. However, they may also lead to an increased number of MDA rounds required to reach the lower threshold and, therefore, increased short-term costs. Collectively, our analyses highlight that lower target Ag thresholds have the potential to assist programs in achieving lymphatic filariasis goals.

Interfacial carbonyl groups of propylene carbonate facilitate the reversible binding of nitrogen dioxide.

The interaction of NO2 with organic interfaces is critical in the development of NO2 sensing and trapping technologies, and equally so to the atmospheric processing of marine and continental aerosol. Recent studies point to the importance of surface oxygen groups in these systems, however the role of specific functional groups on the microscopic level has yet to be fully established. In the present study, we aim to provide fundamental information on the interaction and potential binding of NO2 at atmospherically relevant organic interfaces that may also help inform innovation in NO2 sensing and trapping development. We then present an investigation into the structural changes induced by NO2 at the surface of propylene carbonate (PC), an environmentally relevant carbonate ester. Surface-sensitive vibrational spectra of the PC liquid surface are acquired before, during, and after exposure to NO2 using infrared reflection-absorption spectroscopy (IRRAS). Analysis of vibrational changes at the liquid surface reveal that NO2 preferentially interacts with the carbonyl of PC at the interface, forming a distribution of binding symmetries. At low ppm levels, NO2 saturates the PC surface within 10 minutes and the perturbations to the surface are constant over time during the flow of NO2. Upon removal of NO2 flow, and under atmospheric pressures, these interactions are reversible, and the liquid surface structure of PC recovers completely within 30 min.

The type-I interferon response potentiates seeded tau aggregation and exacerbates tau pathology.

INTRODUCTION: Signatures of a type-I interferon (IFN-I) response are observed in the post mortem brain in Alzheimer's disease (AD) and other tauopathies. However, the effect of the IFN-I response on pathological tau accumulation remains unclear. METHODS: We examined the effects of IFN-I signaling in primary neural culture models of seeded tau aggregation and P301S-tau transgenic mouse models in the context of genetic deletion of the IFN-I receptor (IFNAR). RESULTS: Polyinosinic:polycytidylic acid (PolyI:C), a synthetic analog of viral nucleic acids, evoked a potent cytokine response that enhanced seeded aggregation of tau in an IFN-I-dependent manner. IFN-I-induced vulnerability could be pharmacologically prevented and was intrinsic to neurons. Aged P301S-tau mice lacking Ifnar1 had significantly reduced tau pathology compared to mice with intact IFN signaling. DISCUSSION: We identify a critical role for IFN-I in potentiating tau aggregation. IFN-I is therefore identified as a potential therapeutic target in AD and other tauopathies. HIGHLIGHTS: Type-I IFN (IFN-I) promotes seeded tau aggregation in neural cultures. IFNAR inhibition prevents IFN-I driven sensitivity to tau aggregation. IFN-I driven vulnerability is intrinsic to neurons. Tau pathology is significantly reduced in aged P301S-tau mice lacking IFNAR.

Regenerative potential and limitations in a zebrafish model of hyperglycemia-induced nerve degeneration.

BACKGROUND: Previous work from our lab has described a model of motor nerve degeneration in hyperglycemic zebrafish larvae which resembles mammalian models of diabetic peripheral neuropathy (DPN). Here, we optimized the hyperglycemic-induction protocol, characterized deficits in nerve structure and behavioral function, and then examined the regenerative potential following recovery from the hyperglycemic state. RESULTS: In agreement with our previous work, hyperglycemia induced motor nerve degeneration and behavioral deficits. However, the optimized protocol initiated disruption of tight junctions within the blood-nerve barrier, a phenotype apparent in mammalian models of DPN. Following a 10-day recovery period, regeneration of motor nerve components was apparent, but behavioral deficits persisted. We next examined the effect of hyperglycemia on the musculoskeletal system and found subtle deficits in muscle that resolved following recovery, and robust deficits in the skeletal system which persisted following recovery. CONCLUSION: Here we optimized our previous model of hyperglycemia-induced motor nerve degeneration to more closely align with that observed in mammalian models and then characterized the regenerative potential following recovery from hyperglycemia. Notably, we observed striking impairments to skeletal development, which underscores the global impact hyperglycemia has across systems, and provides a framework for elucidating molecular mechanisms responsible for regenerative events moving forward.

New Insights into Cation- and Temperature-Driven Protein Adsorption to the Air-Water Interface through Infrared Reflection Studies of Bovine Serum Albumin.

The chemistry and structure of the air-ocean interface modulate biogeochemical processes between the ocean and atmosphere and therefore impact sea spray aerosol properties, cloud and ice nucleation, and climate. Protein macromolecules are enriched in the sea surface microlayer and have complex adsorption properties due to the unique molecular balance of hydrophobicity and hydrophilicity. Additionally, interfacial adsorption properties of proteins are of interest as important inputs for ocean climate modeling. Bovine serum albumin is used here as a model protein to investigate the dynamic surface behavior of proteins under several variable conditions including solution ionic strength, temperature, and the presence of a stearic acid (C17COOH) monolayer at the air-water interface. Key vibrational modes of bovine serum albumin are examined via infrared reflectance-absorbance spectroscopy, a specular reflection method that ratios out the solution phase and highlights the aqueous surface to determine, at a molecular level, the surface structural changes and factors affecting adsorption to the solution surface. Amide band reflection absorption intensities reveal the extent of protein adsorption under each set of conditions. Studies reveal the nuanced behavior of protein adsorption impacted by ocean-relevant sodium concentrations. Moreover, protein adsorption is most strongly affected by the synergistic effects of divalent cations and increased temperature.

Structural evolution of water-in-propylene carbonate mixtures revealed by polarized Raman spectroscopy and molecular dynamics.

The liquid structure of systems wherein water is limited in concentration or through geometry is of great interest in various fields such as biology, materials science, and electrochemistry. Here, we present a combined polarized Raman and molecular dynamics investigation of the structural changes that occur as water is added incrementally to propylene carbonate (PC), a polar, aprotic solvent that is important in lithium-ion batteries. Polarized Raman spectra of PC solutions were collected for water mole fractions 0.003 ≤ χwater ≤ 0.296, which encompasses the solubility range of water in PC. The novel approach taken herein provides additional hydrogen bond and solvation characterization of this system that has not been achievable in previous studies. Analysis of the polarized carbonyl Raman band in conjunction with simulations demonstrated that the bulk structure of the solvent remained unperturbed upon the addition of water. Experimental spectra in the O-H stretching region were decomposed through Gaussian fitting into sub-bands and comparison to studies of dilute HOD in D2O. With the aid of simulations, we identified these different bands as water arrangements having different degrees of hydrogen bonding. The observed water structure within PC indicates that water tends to self-aggregate, forming a hydrogen bond network that is distinctly different from the bulk and dependent on concentration. For example, at moderate concentrations, the most likely aggregate structures are chains of water molecules, each with two hydrogen bonds.

Assessing the Mental Wellbeing and Help-Seeking Behaviors of Pre-Veterinary Undergraduates at a Land-Grant Institution.

Recent research conducted within the veterinary profession has reported higher rates of depression and stress than the general US population. While this decline in mental wellbeing has been documented in Doctor of Veterinary Medicine (DVM) students and veterinary professionals, there is a lack of research on the mental wellbeing of the pre-veterinary population. This gap led the authors to conduct a survey in the fall of 2021 utilizing the DASS-21 and ATSPPH-sf inventories to assess the levels of depression, anxiety, stress, and help-seeking stigma in pre-veterinary students to better understand when the decline in veterinary mental wellbeing begins. A pre-test survey was completed by 233 pre-veterinary students in September, and an identical post-test survey was completed by 184 pre-veterinary students in November. From the pre- and post-test data, depression, anxiety, and stress scores increased as students advanced in academic status during their undergraduate degree. Juniors reported the highest averages of depression, anxiety, and stress compared to their peers. In the post-test, sophomores and juniors exhibited higher rates of depression than freshmen, and juniors and seniors exhibited higher rates of stress than freshmen. Current VMCAS applicants exhibited higher levels of stress than non-VMCAS applicants in the pre-test, and lower levels of stress in the post-test. In both the pre-test and post-test data, respondents averaged a neutral attitude toward help-seeking. Based on these results, a decline in pre-veterinary mental wellbeing occurs as students' progress in their undergraduate career and should be further studied to assess its impact on Doctor of Veterinary Medicine and veterinary professional wellbeing.

Reconciling Egg- and Antigen-Based Estimates of Schistosoma mansoni Clearance and Reinfection: A Modeling Study.

BACKGROUND: Despite decades of interventions, 240 million people have schistosomiasis. Infections cannot be directly observed, and egg-based Kato-Katz thick smears lack sensitivity, affected treatment efficacy and reinfection rate estimates. The point-of-care circulating cathodic antigen (referred to from here as POC-CCA+) test is advocated as an improvement on the Kato-Katz method, but improved estimates are limited by ambiguities in the interpretation of trace results. METHOD: We collected repeated Kato-Katz egg counts from 210 school-aged children and scored POC-CCA tests according to the manufacturer's guidelines (referred to from here as POC-CCA+) and the externally developed G score. We used hidden Markov models parameterized with Kato-Katz; Kato-Katz and POC-CCA+; and Kato-Katz and G-Scores, inferring latent clearance and reinfection probabilities at four timepoints over six-months through a more formal statistical reconciliation of these diagnostics than previously conducted. Our approach required minimal but robust assumptions regarding trace interpretations. RESULTS: Antigen-based models estimated higher infection prevalence across all timepoints compared with the Kato-Katz model, corresponding to lower clearance and higher reinfection estimates. Specifically, pre-treatment prevalence estimates were 85% (Kato-Katz; 95% CI: 79%-92%), 99% (POC-CCA+; 97%-100%) and 98% (G-Score; 95%-100%). Post-treatment, 93% (Kato-Katz; 88%-96%), 72% (POC-CCA+; 64%-79%) and 65% (G-Score; 57%-73%) of those infected were estimated to clear infection. Of those who cleared infection, 35% (Kato-Katz; 27%-42%), 51% (POC-CCA+; 41%-62%) and 44% (G-Score; 33%-55%) were estimated to have been reinfected by 9-weeks. CONCLUSIONS: Treatment impact was shorter-lived than Kato-Katz-based estimates alone suggested, with lower clearance and rapid reinfection. At 3 weeks after treatment, longer-term clearance dynamics are captured. At 9 weeks after treatment, reinfection was captured, but failed clearance could not be distinguished from rapid reinfection. Therefore, frequent sampling is required to understand these important epidemiological dynamics.

The Impact of COVID-19 on Pre-Veterinary Opportunities and Recommendations for DVM Admissions.

During the summer of 2020, a survey-based study was conducted at North Carolina State University, a land-grant university, to evaluate the impact of COVID-19 on pre-veterinary students' ability to gain experience hours for Doctor of Veterinary Medicine (DVM) admissions. Of the 286 respondents (47% of the respondent pool), 92% reported losing at least one animal, veterinary, research, extracurricular, or work opportunity due to COVID-19, and 59% were not able to find a replacement. Of the lost experiences, 74 (20.8%) were for academic credit, resulting in 131 total academic credit hours lost, while only 12 credit hours were gained via alternative experiences. Of respondents, 30% (29.7%) identified as applicants of the 2020-2021 Veterinary Medical College Application Service (VMCAS) cycle. More than half (52.6%) of the sample identified being concerned about the strength of their VMCAS experiences due to these lost opportunities. Many respondents reported considering delaying application submissions by taking a gap year (17.5%) or having had their intended graduation timeline affected (14.8%). Since the majority of veterinary colleges utilize a holistic review process, this study provides a basis for understanding the effects of COVID-19 on the duration, depth, and diversity of experiences gained by future DVM applicants. This article also provides recommendations for DVM admissions adaptations based on the outcomes of the data.

Pathogen Dynamics across the Diversity of Aging.

AbstractReproduction, mortality, and immune function often change with age but do not invariably deteriorate. Across the tree of life, there is extensive variation in age-specific performance and changes to key life-history traits. These changes occur on a spectrum from classic senescence, where performance declines with age, to juvenescence, where performance improves with age. Reproduction, mortality, and immune function are also important factors influencing the spread of infectious disease, yet there exists no comprehensive investigation into how the aging spectrum of these traits impacts epidemics. We used a model laboratory infection system to compile an aging profile of a single organism, including traits directly linked to pathogen susceptibility and those that should indirectly alter pathogen transmission by influencing demography. We then developed generalizable epidemiological models demonstrating that different patterns of aging produce dramatically different transmission landscapes: in many cases, aging can reduce the probability of epidemics, but it can also promote severity. This work provides context and tools for use across taxa by empiricists, demographers, and epidemiologists, advancing our ability to accurately predict factors contributing to epidemics or the potential repercussions of senescence manipulation.

Hydration and Hydrogen Bond Order of Octadecanoic Acid and Octadecanol Films on Water at 21 and 1 °C.

The temperature-dependent hydration structure of long-chain fatty acids and alcohols at air-water interfaces has great significance in the fundamental interactions underlying ice nucleation in the atmosphere. We present an integrated theoretical and experimental study of the temperature-dependent vibrational structure and electric field character of the immediate hydration shells of fatty alcohol and acid headgroups. We use a combination of surface-sensitive infrared reflection-absorption spectroscopy (IRRAS), surface potentiometry, and ab initio molecular dynamics simulations to elucidate detailed molecular structures of the octadecanoic acid and octadecanol (stearic acid and stearyl alcohol) headgroup hydration shells at room temperature and near freezing. In experiments, the alcohol at high surface concentration exhibits the largest surface potential; yet we observe a strengthening of the hydrogen-bonding for the solvating water molecules near freezing for both the alcohol and the fatty acid IRRAS experiments. Results reveal that the hydration shells for both compounds screen their polar headgroup dipole moments reducing the surface potential at low surface coverages; at higher surface coverage, the polar headgroups become dehydrated, which reduces the screening, correlating to higher observed surface potential values. Lowering the temperature promotes tighter chain packing and an increase in surface potential. IRRAS reveals that the intra- and intermolecular vibrational coupling mechanisms are highly sensitive to changes in temperature. We find that intramolecular coupling dominates the vibrational relaxation pathways for interfacial water determined by comparing the H2O and the HOD spectra. Using ab initio molecular dynamics (AIMD) calculations on cluster systems of propanol + 6H2O and propionic acid + 10H2O, a spectral decomposition scheme was used to correlate the OH stretching motion with the IRRAS spectral features, revealing the effects of intra- and intermolecular coupling on the spectra. Spectra calculated with AIMD reproduce the red shift and increase in intensity observed in experimental spectra corresponding to the OH stretching region of the first solvation shell. These findings suggest that intra- and intermolecular vibrational couplings strongly impact the OH stretching region at fatty acid and fatty alcohol water interfaces. Overall, results are consistent with ice templating behavior for both the fatty acid and the alcohol, yet the surface potential signature is strongest for the fatty alcohol. These findings develop a better understanding of the complex surface potential and spectral signatures involved in ice templating.

TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination.

Adenovirus has enormous potential as a gene-therapy vector, but preexisting immunity limits its widespread application. What is responsible for this immune block is unclear because antibodies potently inhibit transgene expression without impeding gene transfer into target cells. Here we show that antibody prevention of adenoviral gene delivery in vivo is mediated by the cytosolic antibody receptor TRIM21. Genetic KO of TRIM21 or a single-antibody point mutation is sufficient to restore transgene expression to near-naïve immune levels. TRIM21 is also responsible for blocking cytotoxic T cell induction by vaccine vectors, preventing a protective response against subsequent influenza infection and an engrafted tumor. Furthermore, adenoviral preexisting immunity can lead to an augmented immune response upon i.v. administration of the vector. Transcriptomic analysis of vector-transduced tissue reveals that TRIM21 is responsible for the specific up-regulation of hundreds of immune genes, the majority of which are components of the intrinsic or innate response. Together, these data define a major mechanism underlying the preimmune block to adenovirus gene therapy and demonstrate that TRIM21 efficiently blocks gene delivery in vivo while simultaneously inducing a rapid program of immune transcription.

Sodium-powered stators of the bacterial flagellar motor can generate torque in the presence of phenamil with mutations near the peptidoglycan-binding region.

The bacterial flagellar motor powers the rotation that propels the swimming bacteria. Rotational torque is generated by harnessing the flow of ions through ion channels known as stators which couple the energy from the ion gradient across the inner membrane to rotation of the rotor. Here, we used error-prone PCR to introduce single point mutations into the sodium-powered Vibrio alginolyticus/Escherichia coli chimeric stator PotB and selected for motors that exhibited motility in the presence of the sodium-channel inhibitor phenamil. We found single mutations that enable motility under phenamil occurred at two sites: (i) the transmembrane domain of PotB, corresponding to the TM region of the PomB stator from V. alginolyticus and (ii) near the peptidoglycan binding region that corresponds to the C-terminal region of the MotB stator from E. coli. Single cell rotation assays confirmed that individual flagellar motors could rotate in up to 100 µM phenamil. Using phylogenetic logistic regression, we found correlation between natural residue variation and ion source at positions corresponding to PotB F22Y, but not at other sites. Our results demonstrate that it is not only the pore region of the stator that moderates motility in the presence of ion-channel blockers.

Daphnia magna modifies its gene expression extensively in response to caloric restriction revealing a novel effect on haemoglobin isoform preference.

Caloric restriction (CR) produces clear phenotypic effects within and between generations of the model crustacean Daphnia magna. We have previously established that micro-RNAs and cytosine methylation change in response to CR in this organism, and we demonstrate here that CR has a dramatic effect on gene expression. Over 6,000 genes were differentially expressed between CR and well-fed D. magna, with a bias towards up-regulation of genes under caloric restriction. We identified a highly expressed haemoglobin gene that responds to CR by changing isoform proportions. Specifically, a transcript containing three haem-binding erythrocruorin domains was strongly down-regulated under CR in favour of transcripts containing fewer or no such domains. This change in the haemoglobin mix is similar to the response to hypoxia in Daphnia, which is mediated through the transcription factor hypoxia-inducible factor 1, and ultimately the mTOR signalling pathway. This is the first report of a role for haemoglobin in the response to CR. We also observed high absolute expression of superoxide dismutase (SOD) in normally fed individuals, which contrasts with observations of high SOD levels under CR in other taxa. However, key differentially expressed genes, like SOD, were not targeted by differentially expressed micro-RNAs. Whether the link between haemoglobin and CR occurs in other organisms, or is related to the aquatic lifestyle, remains to be tested. It suggests that one response to CR may be to simply transport less oxygen and lower respiration.

Increased glucose metabolism in Arid5b-/- skeletal muscle is associated with the down-regulation of TBC1 domain family member 1 (TBC1D1).

BACKGROUND: Skeletal muscle has an important role in regulating whole-body energy homeostasis, and energy production depends on the efficient function of mitochondria. We demonstrated previously that AT-rich interactive domain 5b (Arid5b) knockout (Arid5b-/-) mice were lean and resistant to high-fat diet (HFD)-induced obesity. While a potential role of Arid5b in energy metabolism has been suggested in adipocytes and hepatocytes, the role of Arid5b in skeletal muscle metabolism has not been studied. Therefore, we investigated whether energy metabolism is altered in Arid5b-/- skeletal muscle. RESULTS: Arid5b-/- skeletal muscles showed increased basal glucose uptake, glycogen content, glucose oxidation and ATP content. Additionally, glucose clearance and oxygen consumption were upregulated in Arid5b-/- mice. The expression of glucose transporter 1 (GLUT1) and 4 (GLUT4) in the gastrocnemius (GC) muscle remained unchanged. Intriguingly, the expression of TBC domain family member 1 (TBC1D1), which negatively regulates GLUT4 translocation to the plasma membrane, was suppressed in Arid5b-/- skeletal muscle. Coimmunofluorescence staining of the GC muscle sections for GLUT4 and dystrophin revealed increased GLUT4 localization at the plasma membrane in Arid5b-/- muscle. CONCLUSIONS: The current study showed that the knockout of Arid5b enhanced glucose metabolism through the downregulation of TBC1D1 and increased GLUT4 membrane translocation in skeletal muscle.

Disruption of peripheral nerve development in a zebrafish model of hyperglycemia.

Diabetes mellitus-induced hyperglycemia is associated with a number of pathologies such as retinopathy, nephropathy, delayed wound healing, and diabetic peripheral neuropathy (DPN). Approximately 50% of patients with diabetes mellitus will develop DPN, which is characterized by disrupted sensory and/or motor functioning, with treatment limited to pain management. Zebrafish (Danio rerio) are an emerging animal model used to study a number of metabolic disorders, including diabetes. Diabetic retinopathy, nephropathy, and delayed wound healing have all been demonstrated in zebrafish. Recently, our laboratory has demonstrated that following the ablation of the insulin-producing ß-cells of the pancreas (and subsequent hyperglycemia), the peripheral nerves begin to show signs of dysregulation. In this study, we take a different approach, taking advantage of the transdermal absorption abilities of zebrafish larvae to extend the period of hyperglycemia. Following 5 days of 60 mM d-glucose treatment, we observed motor axon defasciculation, disturbances in perineurial glia sheath formation, decreased myelination of motor axons, and sensory neuron mislocalization. This study extends our understanding of the structural changes of the peripheral nerve following induction of hyperglycemia and does so in an animal model capable of potential DPN drug discovery in the future.NEW & NOTEWORTHY Zebrafish are emerging as a robust model system for the study of diabetic complications such as retinopathy, nephropathy, and impaired wound healing. We present a novel model of diabetic peripheral neuropathy in zebrafish in which the integrity of the peripheral nerve is dysregulated following the induction of hyperglycemia. By using this model, future studies can focus on elucidating the underlying molecular mechanisms currently unknown.

Acute effects of hyperglycemia on the peripheral nervous system in zebrafish ( Danio rerio) following nitroreductase-mediated ß-cell ablation.

Diabetic peripheral neuropathy (DPN) is estimated to affect 50% of diabetic patients. Although DPN is highly prevalent, molecular mechanisms remain unknown and treatment is limited to pain relief and glycemic control. We provide a novel model of acute DPN in zebrafish ( Danio rerio) larvae. Beginning 5 days postfertilization (dpf), zebrafish expressing nitroreductase in their pancreatic ß-cells were treated with metronidazole (MTZ) for 48 h and checked for ß-cell ablation 7 dpf. In experimental design, this was meant to serve as proof of concept that ß-cell ablation and hyperglycemia are possible at this time point, but we were surprised to find changes in both sensory and motor nerve components. Compared with controls, neurod+ sensory neurons were often observed outside the dorsal root ganglia in MTZ-treated fish. Fewer motor nerves were properly ensheathed by nkx2.2a+ perineurial cells, and tight junctions were disrupted along the motor nerve in MTZ-treated fish compared with controls. Not surprisingly, the motor axons of the MTZ-treated group were defasciculated compared with the control group, myelination was attenuated, and there was a subtle difference in Schwann cell number between the MTZ-treated and control group. All structural changes occurred in the absence of behavioral changes in the larvae at this time point, suggesting that peripheral nerves are influenced by acute hyperglycemia before becoming symptomatic. Moving forward, this novel animal model of DPN will allow us to access the molecular mechanisms associated with the acute changes in the hyperglycemic peripheral nervous system, which may help direct therapeutic approaches.

Prescription of High-Dose Opioids Among People Living with HIV in British Columbia, Canada.

People living with HIV (PLHIV) often experience pain for which opioid medications may be prescribed. Thus, these individuals are particularly vulnerable to opioid-related harms, including overdose, misuse, and addiction, particularly when prescribed at high doses. We used a comprehensive linked population-level database of PLHIV in British Columbia (BC) to identify demographic and clinical characteristics associated with being prescribed any high-dose opioid analgesic, defined as > 90 daily morphine milligram equivalents (MME/day). Among PLHIV who were prescribed opioids between 1996 and 2015 (n = 10,780), 28.2% received prescriptions of > 90 MME/day at least once during the study period. Factors positively associated with being prescribed high-dose opioid analgesics included: co-prescription of benzodiazepines (adjusted odds ratio [AOR] = 1.14; 95% confidence interval 1.11-1.17); presence of an AIDS-defining illness (ADI; AOR = 1.78; 95% CI 1.57-2.02); seen by an HIV specialist (AOR = 1.24; 95% CI 1.20-1.29); substance use disorder (AOR = 1.46; 95% CI 1.25-1.71); and more recent calendar year (AOR = 1.05; 95% CI 1.04-1.06). Given the known risks associated with high-dose opioid prescribing, future research efforts should focus on the clinical indication and outcomes associated with these prescribing practices.

Disease spread in age structured populations with maternal age effects.

Fundamental ecological processes, such as extrinsic mortality, determine population age structure. This influences disease spread when individuals of different ages differ in susceptibility or when maternal age determines offspring susceptibility. We show that Daphnia magna offspring born to young mothers are more susceptible than those born to older mothers, and consider this alongside previous observations that susceptibility declines with age in this system. We used a susceptible-infected compartmental model to investigate how age-specific susceptibility and maternal age effects on offspring susceptibility interact with demographic factors affecting disease spread. Our results show a scenario where an increase in extrinsic mortality drives an increase in transmission potential. Thus, we identify a realistic context in which age effects and maternal effects produce conditions favouring disease transmission.