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Abstract Adolescents with callous unemotional (CU) traits are at risk for poor quality-of-life outcomes such as incarceration, suicide, and psychopathy. It is currently unknown which treatments are implemented with CU adolescents specifically and which elements make up these interventions. A narrative systematic review was used to identify the treatments and common elements used with CU adolescents (12–18 years). Eligible studies were randomized controlled trials and quasi-experimental studies evaluating psychosocial interventions, delivered within a clinical context, and directed towards the adolescent or their family. Eight studies with 1291 participants were included. Significant decreases in CU traits were demonstrated only in a minority of studies. The most utilized practice elements were set goals for treatment, practice interpersonal/communication skills, prepare for termination, and teach parents skills and strategies; the most utilized process elements were formal therapy, practice exercises, important others, and flexible/adaptive. A majority of the studies did not report an implementation element. While theoretical frameworks for CU children are employed with CU adolescents, there is still uncertainty regarding their suitability for this age group. Given the limited empirical evidence, there is a critical need for further exploration.

Abstract Chronic wasting disease (CWD), a prion disease affecting cervids, has been known in North America (NA) since the 1960s and emerged in Norway in 2016. Surveillance and studies have revealed that there are different forms of CWD in Fennoscandia: contagious CWD in Norwegian reindeer and sporadic CWD in moose and red deer. Experimental studies have demonstrated that NA CWD prions can infect various species, but thus far, there have been no reports of natural transmission to non-cervid species. In vitro and laboratory animal studies of the Norwegian CWD strains suggest that these strains are different from the NA strains. In this work, we describe the intracerebral transmission of reindeer CWD to six scrapie-susceptible sheep. Detection methods included immunohistochemistry (IHC), western blot (WB), enzyme-linked immunosorbent assay (ELISA), real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA). In the brain, grey matter vacuolation was limited, while all sheep exhibited vacuolation of the white matter. IHC and WB conventional detection techniques failed to detect prions; however, positive seeding activity with the RT-QuIC and PMCA amplification techniques was observed in the central nervous system of all but one sheep. Prions were robustly amplified in the lymph nodes of all animals, mainly by RT-QuIC. Additionally, two lymph nodes were positive by WB, and one was positive by ELISA. These findings suggest that sheep can propagate reindeer CWD prions after intracerebral inoculation, resulting in an unusual disease phenotype and prion distribution with a low amount of detectable prions.

ABSTRACT INTRODUCTION: Depressive symptoms are associated with Alzheimer’s disease (AD), but their neurobiological and neuropsychological correlates remain poorly understood. We investigate if depressive symptoms are associated with amyloid (Aβ) pathology and cognition in predementia AD. METHODS: We included Subjective Cognitive Decline (SCD, n= 160) and Mild Cognitive Impairment (MCI, n=192) from the Dementia Disease Initiation cohort. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS-15). Aβ pathology was determined using cerebrospinal fluid (CSF) Aβ42/40 ratio. Associations between depressive symptoms and cognition were assessed with logistic regression. RESULTS: Only the Aβ negative MCI group (MCI-Aβ-) was associated with depressive symptoms (OR=2.65, p=.005). Depressive symptoms were associated with worse memory in MCI-Aβ- (OR=0.94, p=.039), but with better performance in MCI-Aβ+ (OR=1.103, p=.001). DISCUSSION: Our results suggest that depressive symptoms in MCI are neither associated with Aβ pathology, nor AD-associated memory impairment. However, memory impairment in non-AD MCI may relate to depressive symptoms.

Background:. Shaft fractures of the femur are commonly treated with intramedullary nailing, which can release bone marrow emboli into the bloodstream. Emboli can travel to the lungs, impairing gas exchange and causing inflammation. Occasionally, emboli traverse from the pulmonary to the systemic circulation, hindering perfusion and resulting in injuries such as heart and brain infarctions, known as fat embolism syndrome. We studied the extent of systemic bone marrow embolization in a pig model. Methods:. Twelve anesthetized pigs underwent bilateral intramedullary nailing of the femur, while 3 animals served as sham controls. Monitoring included transesophageal echocardiography (TEE), pulse oximetry, electrocardiography, arterial blood pressure measurement, and blood gas and troponin-I analysis. After surgery, animals were monitored for 240 minutes before euthanasia. Post mortem, the heart, lungs, and brain were biopsied. Results:. Bone marrow emboli were found in the heart and lungs of all 12 of the pigs that underwent intramedullary nailing and in the brains of 11 of them. No emboli were found in the sham group. The pigs subjected to intramedullary nailing exhibited significant hypoxia (PaO2/FiO2 ratio, 410 mm Hg [95% confidence interval (CI), 310 to 510) compared with the sham group (594 mm Hg [95% CI, 528 to 660]). The nailing group exhibited ST-segment alterations consistent with myocardial ischemia and a significant increase in the troponin-I level compared with the sham group (1,580 ng/L [95% CI, 0 to 3,456] versus 241 ng/L [95% CI, 0 to 625] at the 240-minute time point; p = 0.005). TEE detected emboli in the right ventricular outflow tract, but not systemically, in the nailing group. Conclusions:. Bilateral intramedullary nailing caused bone marrow emboli in the lungs and systemic emboli in the heart and brain in this pig model. The observed clinical manifestations were consistent with coronary and pulmonary emboli. TEE detected pulmonary but not systemic embolization. Clinical Relevance:. Femoral intramedullary nailing in humans is likely to result in embolization as described in our pig model. Focused monitoring is necessary for detection of fat embolism syndrome. Absence of visual emboli in the left ventricle on TEE does not exclude the occurrence of systemic bone marrow emboli.

Purpose: Adolescence is a sensitive period for developing mental health problems. Interventions targeting emotion regulation have shown promising transdiagnostic effects for this group, but optimization efforts are called for. In the current study, we used an element-based approach to identify potentially active ingredients in interventions measuring emotion regulation, to guide further optimization. Methods: We coded practice elements in 30 studies based on a systematic review of mental health interventions measuring emotion regulation in adolescents (N = 2,389 participants, mean age 13-17 years). Using a three-level modeling approach, we then investigated the difference in effect on emotion regulation between studies of interventions with and without these practice elements. Results: We identified 75 practice elements and 15 element categories used in the included interventions. Results showed significantly stronger effects on emotion regulation when interventions included the practice elements Setting goals for treatment (difference in d = 0.40, 95% CI [0.09, 0.70], p = 0.012) and Psychoeducation about acceptance (difference in d = 0.58, 95% CI [0.09, 1.07], p = 0.021). Furthermore, a total of 11 elements and four overall categories were identified as potentially active ingredients, based on an effect size difference of > 0.20 between interventions with and without the elements. Conclusion: The results can direct experimental research into the selection of practices that are most likely key to mechanisms of change in interventions addressing emotion regulation for adolescents. The challenge of measuring emotion regulation is discussed.

We investigate data from an acoustic Doppler current profiler deployed in a constricted ocean channel showing a tidally dominated flow with intermittent velocity extrema during outflow from the constriction but not during inflow. A 2D numerical ocean model forced by tides is used to examine the spatial flow structure and underlying dynamical processes. We find that flow-separation eddies generated near the tightest constriction point form a dipole pair which propagates downstream and drives the observed intermittent flow variability. The eddies, which are generated by an along-channel adverse pressure gradient, spin up for some time near the constriction until they develop local low pressures in their centers that are strong enough to modify the background along-channel pressure gradient significantly. When the dipole has propagated some distance away from the constriction, the conditions for flow separation are recovered, and new eddies are formed.

Abstract Background Chronic wasting disease (CWD) is a prion disease of cervids first reported in North America in the 1960s. In Europe, CWD was first diagnosed in 2016 in a wild reindeer in Norway. Detection of two more cases in the same mountain area led to the complete culling of this partially confined reindeer population of about 2400 animals. A total of 19 CWD positive animals were identified. The affected area is extensively used for the grazing of sheep during summers. There are many mineral licks intended for sheep in the area, but these have also been used by reindeer. This overlap in area use raised concerns for cross-species prion transmission between reindeer and sheep. In this study, we have used global positioning system (GPS) data from sheep and reindeer, including tracking one of the CWD positive reindeer, to investigate spatial and time-relevant overlaps between these two species. Since prions can accumulate in lymphoid follicles following oral uptake, samples of gut-associated lymphoid tissue (GALT) from 425 lambs and 78 adult sheep, which had grazed in the region during the relevant timeframe, were analyzed for the presence of prions. The recto-anal mucosa associated lymphoid tissue (RAMALT) from all the animals were examined by histology, immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA), and the ileal Peyer's patch (IPP) from a subsample of 37 lambs were examined by histology and IHC, for the detection of prions. Results GPS data showed an overlap in area use between the infected reindeer herd and the sheep. In addition, the GPS positions of an infected reindeer and some of the sampled sheep showed temporospatial overlap. No prions were detected in the GALT of the investigated sheep even though the mean lymphoid follicle number in RAMALT and IPP samples were high. Conclusion The absence of prions in the GALT of sheep that have shared pasture with CWD-infected reindeer, may suggest that transmission of this novel CWD strain to sheep does not easily occur under the conditions found in these mountains. We document that the lymphoid follicle rich RAMALT could be a useful tool to screen for prions in sheep.

Adolescents with callous unemotional (CU) traits are at risk for poor quality-of-life outcomes such as incarceration, suicide, and psychopathy. It is currently unknown which treatments are implemented with CU adolescents specifically and which elements make up these interventions. A narrative systematic review was used to identify the treatments and common elements used with CU adolescents (12–18 years). Eligible studies were randomized controlled trials and quasi-experimental studies evaluating psychosocial interventions, delivered within a clinical context, and directed towards the adolescent or their family. Eight studies with 1291 participants were included. Significant decreases in CU traits were demonstrated only in a minority of studies. The most utilized practice elements were set goals for treatment, practice interpersonal/communication skills, prepare for termination, and teach parents skills and strategies; the most utilized process elements were formal therapy, practice exercises, important others, and flexible/adaptive. A majority of the studies did not report an implementation element. While theoretical frameworks for CU children are employed with CU adolescents, there is still uncertainty regarding their suitability for this age group. Given the limited empirical evidence, there is a critical need for further exploration. [ABSTRACT FROM AUTHOR]

Experiential learning (EL) has great potential to prepare students to work on interdisciplinary and global challenges across traditional boundaries, as well as support them in the development of reflective skills. In this study, we explore reflection as a central element for EL in the university wide interdisciplinary course Experts in Teamwork (EiT). Based upon 17 years of experience with the development of EiT, perspectives from the literature, and critically analyzing current practices, we describe two key findings from this ongoing exploration: the need to develop a framework for such a course and the need for training of teaching staff.

Stunning by carbon dioxide (CO2) inhalation is controversial because it is associated with vigorous movements and behaviours which may or may not be conscious reactions. Furthermore, it is unknown whether some behaviours might indicate the transition into unconsciousness. Our study objective was to investigate the loss of consciousness during CO2 stunning by linking physiological variables (in particular pH, PaO2 and PaCO2) to the onset of observed behaviours. A total of 11 cross-bred pigs were studied. A tracheostomy tube, venous and arterial cannulae were placed under sevoflurane anaesthesia. After recovery from this, and a “wash out” period of at least 30 min, arterial blood samples were taken (and baseline values established) before 90–95% CO2 in medical air was administered through the tracheostomy tube. Subsequent behaviours were video-recorded and key physiological variables were evaluated using an anaesthetic monitor and the frequent sampling of arterial blood (albeit with inconsistent inter-sample intervals). After the study, behaviours were classified in an ethogram. At the onset of behaviours categorised as “vigorous movement extremities”, “opisthotonos” and “agonal gasping” pH values (range) were: 6.74–7.34; 6.66–6.96 and 6.65–6.87, while PaCO2 (kPa) was 4.6–42.2, 24.4–51.4 and 29.1–47.6. Based upon these values, we conclude that the pigs were probably unconscious at the onset of “opisthotonos” and “agonal gasping”, but some were probably conscious at the onset of “vigorous movements”.

During recent years, there has been a renewed interest in establishing farming of Atlantic cod (Gadus morhua) in Norway. However, a fatal abdominal disorder compromises animal welfare and causes economic losses. A similar problem was present during a previous attempt to establish Atlantic cod farming more than a decade ago. In this paper, we provide the first in‐depth description of this intestinal disorder, which is correctly denoted 'strangulating obstruction'. In affected fish, part of the intestine is permanently entrapped (incarcerated) under fibrous strands in the mesentery. The entrapment interferes with blood flow and physically blocks the intestine, causing a strangulating obstruction with severe venous congestion and ischemia of the intestinal wall. Furthermore, comparison of macroscopical and histological anatomy of farmed and wild Atlantic cod is presented and risk factors associated with the anatomical differences are discussed. [ABSTRACT FROM AUTHOR]

Chronic wasting disease (CWD), a prion disease affecting cervids, has been known in North America (NA) since the 1960s and emerged in Norway in 2016. Surveillance and studies have revealed that there are different forms of CWD in Fennoscandia: contagious CWD in Norwegian reindeer and sporadic CWD in moose and red deer. Experimental studies have demonstrated that NA CWD prions can infect various species, but thus far, there have been no reports of natural transmission to non-cervid species. In vitro and laboratory animal studies of the Norwegian CWD strains suggest that these strains are different from the NA strains. In this work, we describe the intracerebral transmission of reindeer CWD to six scrapie-susceptible sheep. Detection methods included immunohistochemistry (IHC), western blot (WB), enzyme-linked immunosorbent assay (ELISA), real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA). In the brain, grey matter vacuolation was limited, while all sheep exhibited vacuolation of the white matter. IHC and WB conventional detection techniques failed to detect prions; however, positive seeding activity with the RT-QuIC and PMCA amplification techniques was observed in the central nervous system of all but one sheep. Prions were robustly amplified in the lymph nodes of all animals, mainly by RT-QuIC. Additionally, two lymph nodes were positive by WB, and one was positive by ELISA. These findings suggest that sheep can propagate reindeer CWD prions after intracerebral inoculation, resulting in an unusual disease phenotype and prion distribution with a low amount of detectable prions. [ABSTRACT FROM AUTHOR]

Objective: The Delis-Kaplan Executive Function System (D-KEFS) Color-Word-Interference Test (CWIT; AKA Stroop test) is a widely used measure of processing speed and executive function. While test materials and instructions have been translated to Norwegian, only American age-adjusted norms from D-KEFS are available in Norway. We here develop norms in a sample of 1011 Norwegians between 20 and 85 years. We provide indexes for stability over time and assess demographic adjustments applying the D-KEFS norms. Method: Participants were healthy Norwegian adults from Center for Lifespan Changes in Brain and Cognition (LCBC) (n = 899), the Dementia Disease Initiation (n = 77), and Oslo MCI (n = 35). Using regression-based norming, we estimated linear and non-linear effects of age, education, and sex on the CWIT 1-4 subtests. Stability over time was assessed with intraclass correlation coefficients (ICC). The normative adjustment of the D-KEFS norms was assessed with linear regression models. Results: Increasing age was associated with slower completion on all CWIT subtests in a non-linear fashion (accelerated lowering of performance with older age). Women performed better on CWIT-1&3. Higher education predicted faster completion time on CWIT-3&4. The original age-adjusted norms from D-KEFS did not adjust for sex or education. Furthermore, we observed significant, albeit small effects of age on all CWIT subtests. ICC analyses indicated moderate to good stability over time. Conclusion: We present demographically adjusted regression-based norms and stability indexes for the D-KEFS CWIT subtests. US D-KEFS norms may be inaccurate for Norwegians with high or low educational attainment, especially women. [ABSTRACT FROM AUTHOR]

Abstract Prion diseases are progressive and fatal, neurodegenerative disorders described in humans and animals. According to the “protein-only” hypothesis, the normal host-encoded prion protein (PrPC) is converted into a pathological and infectious form (PrPSc) in these diseases. Transgenic knockout models have shown that PrPC is a prerequisite for the development of prion disease. In Norwegian dairy goats, a mutation (Ter) in the prion protein gene (PRNP) effectively blocks PrPC synthesis. We inoculated 12 goats (4 PRNP +/+, 4 PRNP +/Ter, and 4 PRNP Ter/Ter) intracerebrally with goat scrapie prions. The mean incubation time until clinical signs of prion disease was 601 days post-inoculation (dpi) in PRNP +/+ goats and 773 dpi in PRNP +/Ter goats. PrPSc and vacuolation were similarly distributed in the central nervous system (CNS) of both groups and observed in all brain regions and segments of the spinal cord. Generally, accumulation of PrPSc was limited in peripheral organs, but all PRNP +/+ goats and 1 of 4 PRNP +/Ter goats were positive in head lymph nodes. The four PRNP Ter/Ter goats remained healthy, without clinical signs of prion disease, and were euthanized 1260 dpi. As expected, no accumulation of PrPSc was observed in the CNS or peripheral tissues of this group, as assessed by immunohistochemistry, enzyme immunoassay, and real-time quaking-induced conversion. Our study shows for the first time that animals devoid of PrPC due to a natural mutation do not propagate prions and are resistant to scrapie. Clinical onset of disease is delayed in heterozygous goats expressing about 50% of PrPC levels.

A number of inherited ataxias is known in humans, with more than 250 loci implicated, most of which are included in human ataxia screening panels. Anecdotally, cases of ataxia in the Norwegian elkhound black have been known for the last 40 years. Affected puppies from three litters were clinically and neurologically examined, and postmortem samples were collected for morphological studies, including ultrastructural analyses. The puppies displayed vestibulocerebellar neurological signs and had degenerative histopathological alterations in cerebellum and brain stem. Three affected dogs, each from different litters, as well as both parents and one healthy littermate from each litter, were whole genome sequenced. Through variant calling we discovered a disease-associated 1 bp deletion in HACE1 (CFA12), resulting in a frameshift at codon 333 and a premature stop codon at codon 366. The perfect association combined with the predicted significant molecular effect, strongly suggest that we have found the causative mutation for Norwegian elkhound black ataxia. We have identified a novel candidate gene for ataxia where dogs can serve as a spontaneous model for improved understanding of ataxia, also in human.

Introduction: The Rey–Osterrieth Complex Figure Test (RCFT) is one of the most commonly used neuropsychological tests in Sweden and Norway. However, no publications provide normative data for this population. The objective of this study was to present demographically adjusted norms for a Swedish and Norwegian population and to evaluate these in an independent comparison group. Methods: The RCFT was administrated to 344 healthy controls recruited from the Swedish Gothenburg MCI study, the Norwegian Dementia Disease Initiation study, and the Swedish Cardiopulmonary Bioimage Study. Age ranged from 49 to 77 years (mean = 62.4 years, SD = 5.0 years), and education ranged from 6 to 24 years (mean = 13.3 years, SD = 3.0 years). Using a regression‐based procedure, we investigated the effects of age, sex, and years of education on test performance. We compared and evaluated our Swedish and Norwegian norms with North American norms in an independent comparison group of 145 individuals. Results: In healthy controls, age and education were associated with performance on the RCFT. When comparing normative RCFT performance in an independent comparison group, North American norms generally overestimated immediate and delayed recall performance. In contrast, our Swedish and Norwegian norms appear to better take into account factors of age and education. Conclusions: We presented demographically adjusted norms for the RCFT in a Swedish and Norwegian sample. This is the first normative study of the RCFT that presents normative data for this population. In addition, we showed that North American norms might produce inaccurate normative estimations in an independent comparison group. [ABSTRACT FROM AUTHOR]

Abstract Background Mutations in the N-myc downstream-regulated gene 1 (NDRG1) can cause degenerative polyneuropathy in humans, dogs, and rodents. In humans, this motor and sensory neuropathy is known as Charcot-Marie-Tooth disease type 4D, and it is assumed that analogous canine diseases can be used as models for this disease. NDRG1 is also regarded as a metastasis-suppressor in several malignancies. The tissue distribution of NDRG1 has been described in humans and rodents, but this has not been studied in the dog. Results By immunolabeling and Western blotting, we present a detailed mapping of NDRG1 in dog tissues and primary canine Schwann cell cultures, with particular emphasis on peripheral nerves. High levels of phosphorylated NDRG1 appear in distinct subcellular localizations of the Schwann cells, suggesting signaling-driven rerouting of the protein. In a nerve from an Alaskan malamute homozygous for the disease-causing Gly98Val mutation in NDRG1, this signal was absent. Furthermore, NDRG1 is present in canine epithelial cells, predominantly in the cytosolic compartment, often with basolateral localization. Constitutive expression also occurs in mesenchymal cells, including developing spermatids that are transiently positive for NDRG1. In some cells, NDRG1 localize to centrosomes. Conclusions Overall, canine NDRG1 shows a cell and context-dependent localization. Our data from peripheral nerves and primary Schwann cell cultures suggest that the subcellular localization of NDRG1 in Schwann cells is dynamically influenced by signaling events leading to reversible phosphorylation of the protein. We propose that disease-causing mutations in NDRG1 can disrupt signaling in myelinating Schwann cells, causing disturbance in myelin homeostasis and axonal-glial cross talk, thereby precipitating polyneuropathy.

Semantic verbal fluency is among the most employed tasks in cognitive aging research and substantial work is devoted to understanding the underlying mechanisms behind age-related differences at the neural and behavioral levels. The present investigation aimed to evaluate the role of moderating variables, such as age, sex, MMSE, and proxies of cognitive reserve (CR) on the hemodynamic response evoked by semantic verbal fluency in healthy young and healthy older adults. So far, no study has been conducted to this end. To elucidate the exclusive effect of the mentioned variables on brain activation during semantic fluency, finger tapping was included as a control task. Results showed that disregarding adjustments for age, older adults displayed important parietal activations during semantic fluency as well as during finger-tapping. Specifically, the anterior intra-parietal sulcus (IPS) and left inferior parietal lobule (IPL) were areas activated in both tasks in the older group. Younger adults, only displayed parietal activations related to age and sex when these demographics were employed as predictors. Concerning proxies of CR in semantic fluency, the only vocabulary was an important moderator in both age groups. Higher vocabulary scores were associated with lesser activation in occipital areas. Education did not show significant correlations with brain activity during semantic fluency in any of the groups. However, both CR proxies were significantly correlated to brain activations of older adults during finger tapping. Specifically, vocabulary was associated with frontal regions, while education correlated with parietal lobe and cingulate gyrus. Finally, the effects of MMSE were mostly observed on brain activation of older adults in both tasks. These findings demonstrate that the effects of moderating variables on shaping brain activation are intricate and not exclusive of complex verbal tasks. Thus, before adjusting for “nuisance variables,” their importance needs to be established. This is especially true for samples including older adults for whom a motor task may be a demanding operation due to normal age-related processes of dedifferentiation.

Abstract A homozygous mutation has been identified in the N-myc downstream-regulated gene 1 (NDRG1) in recent cases of polyneuropathy in Alaskan malamute dogs from the Nordic countries and USA. The objective of the present study was to determine if cases diagnosed 30–40 years ago with polyneuropathy in the Alaskan malamute breed in Norway had the same hereditary disease as the recent cases. Fourteen historical cases and 12 recently diagnosed Alaskan malamute dogs with hereditary polyneuropathy, and their parents and littermates (n = 88) were included in this study (total n = 114). After phenotyping of historical and recent cases, NDRG1 genotyping was performed using DNA extracted from archived material from five Norwegian dogs affected by the disease in the late 1970s and 1980s. In addition, pedigrees were analysed. Our study concluded that historical and recent phenotypic polyneuropathy cases were carrying the same NDRG1-mutation. The pedigree analysis showed that all affected Alaskan malamute cases with polyneuropathy could be traced back to one common ancestor of North American origin. By this study, a well-documented example of the silent transmission of recessive disease-causing alleles through many generations is provided, demonstrated by the re-emergence of a phenotypically and genetically uniform entity in the Scandinavian Alaskan malamute population.

We investigate data from an acoustic Doppler current profiler deployed in a constricted ocean channel showing a tidally dominated flow with intermittent velocity extrema during outflow from the constriction but not during inflow. A 2D numerical ocean model forced by tides is used to examine the spatial flow structure and underlying dynamical processes. We find that flow-separation eddies generated near the tightest constriction point form a dipole pair which propagates downstream and drives the observed intermittent flow variability. The eddies, which are generated by an along-channel adverse pressure gradient, spin up for some time near the constriction until they develop local low pressures in their centers that are strong enough to modify the background along-channel pressure gradient significantly. When the dipole has propagated some distance away from the constriction, the conditions for flow separation are recovered, and new eddies are formed. [ABSTRACT FROM AUTHOR]

The cellular prion protein PrPC is highly expressed in neurons, but also present in non-neuronal tissues, including the testicles and spermatozoa. Most immune cells and their bone marrow precursors also express PrPC. Clearly, this protein operates in highly diverse cellular contexts. Investigations into putative stress-protective roles for PrPC have resulted in an array of functions, such as inhibition of apoptosis, stimulation of anti-oxidant enzymes, scavenging roles, and a role in nuclear DNA repair. We have studied stress resilience of spermatozoa and peripheral blood mononuclear cells (PBMCs) derived from non-transgenic goats that lack PrPC (PRNPTer/Ter) compared with cells from normal (PRNP+/+) goats. Spermatozoa were analyzed for freeze tolerance, DNA integrity, viability, motility, ATP levels, and acrosome intactness at rest and after acute stress, induced by Cu2+ ions, as well as levels of reactive oxygen species (ROS) after exposure to FeSO4 and H2O2. Surprisingly, PrPC-negative spermatozoa reacted similarly to normal spermatozoa in all read-outs. Moreover, in vitro exposure of PBMCs to Doxorubicin, H2O2 and methyl methanesulfonate (MMS), revealed no effect of PrPC on cellular survival or global accumulation of DNA damage. Similar results were obtained with human neuroblastoma (SH-SY5Y) cell lines stably expressing varying levels of PrPC. RNA sequencing of PBMCs (n = 8 of PRNP+/+ and PRNPTer/Ter) showed that basal level expression of genes encoding DNA repair enzymes, ROS scavenging, and antioxidant enzymes were unaffected by the absence of PrPC. Data presented here questions the in vitro cytoprotective roles previously attributed to PrPC, although not excluding such functions in other cell types or tissues during inflammatory stress.

A naturally occurring mutation in the PRNP gene of Norwegian dairy goats terminates synthesis of the cellular prion protein (PrPC), rendering homozygous goats (PRNPTer/Ter) devoid of the protein. Although PrPC has been extensively studied, particularly in the central nervous system, the biological role of PrPC remains incompletely understood. Here, we examined whether loss of PrPC affects the initial stage of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Acute pulmonary inflammation was induced by intravenous injection of LPS (Escherichia coli O26:B6) in 16 goats (8 PRNPTer/Ter and 8 PRNP+/+). A control group of 10 goats (5 PRNPTer/Ter and 5 PRNP+/+) received sterile saline. Systemic LPS challenge induced sepsis-like clinical signs including tachypnea and respiratory distress. Microscopic examination of lungs revealed multifocal areas with alveolar hemorrhages, edema, neutrophil infiltration, and higher numbers of alveolar macrophages, with no significant differences between PRNP genotypes. A total of 432 (PRNP+/+) and 596 (PRNPTer/Ter) genes were differentially expressed compared with the saline control of the matching genotype. When assigned to gene ontology categories, biological processes involved in remodeling of the extracellular matrix (ECM), were exclusively enriched in PrPC-deficient goats. These genes included a range of collagen-encoding genes, and proteases such as matrix metalloproteinases (MMP1, MMP2, MMP14, ADAM15) and cathepsins. Several proinflammatory upstream regulators (TNF-α, interleukin-1β, IFN-γ) showed increased activation scores in goats devoid of PrPC. In conclusion, LPS challenge induced marked alterations in the lung tissue transcriptome that corresponded with histopathological and clinical findings in both genotypes. The increased activation of upstream inflammatory regulators and enrichment of ECM components could reflect increased inflammation in the absence of PrPC. Further studies are required to elucidate whether these alterations may affect the later reparative phase of ALI.