Background
Neurofilament light chain (NfL) is a neuron‐specific cytoskeletal protein expressed in axons. Damaged axons of the central nervous system release NfLs into the cerebrospinal fluid (CSF) ...and the blood. In humans with neurologic diseases, NfL is used as a biomarker.
Objectives
To identify the potential of NfL as a supportive tool for the diagnosis, prognosis, and monitoring of meningoencephalitis of unknown etiology (MUE) in dogs.
Animals
Twenty‐six client‐owned healthy dogs, 10 normal Beagle dogs, and 38 client‐owned MUE dogs.
Methods
Cohort study. The concentrations of NfL in serum and CSF were measured using single‐molecule array technology.
Results
Median NfL concentration was significantly higher in MUE dogs (serum, 125 pg/mL; CSF, 14 700 pg/mL) than in healthy dogs (serum, 11.8 pg/mL, P < .0001; CSF, 1410 pg/mL, P = .0002). The areas under the receiver operating characteristic curves of serum and CSF NfL concentrations were 0.99 and 0.95, respectively. The cut‐off values were 41.5 pg/mL (serum) and 4005 pg/mL (CSF) for differentiating between healthy and MUE dogs, with sensitivities of 89.19% and 90%, respectively, and specificities of 96.97% and 100%, respectively. The NfL concentration showed a significant decrease (pretreatment, 122 pg/mL; posttreatment, 36.6 pg/mL; P = .02) in the good treatment‐response group and a significant increase (pretreatment, 292.5 pg/mL; posttreatment, 1880 pg/mL, P = .03) in the poor treatment‐response group.
Conclusions and Clinical importance
Neurofilament light chain is a potential biomarker for diagnosing MUE and evaluating response to treatment.
Anaplasma spp. are tick-borne Gram-negative obligate intracellular bacteria that infect humans and a wide range of animals. Anaplasma capra has emerged as a human pathogen; however, little is known ...about the occurrence and genetic identity of this agent in wildlife. The present study aimed to determine the infection rate and genetic profile of this pathogen in wild animals in the Republic of Korea.
A total of 253 blood samples 198 from Korean water deer (Hydropotes inermis argyropus), 53 from raccoon dogs (Nyctereutes procyonoides) and one sample each from a leopard cat (Prionailurus bengalensis) and a roe deer (Capreolus pygargus) were collected at Chungbuk Wildlife Center during the period 2015-2018. Genomic DNA was extracted from the samples and screened for presence of Anaplasma species by PCR/sequence analysis of 429 bp of the 16S rRNA gene marker. Anaplasma capra-positive isolates were genetically profiled by amplification of a longer fragment of 16S rRNA (rrs) as well as partial sequences of citrate synthase (gltA), heat-shock protein (groEL), major surface protein 2 (msp2) and major surface protein 4 (msp4). Generated sequences of each gene marker were aligned with homologous sequences in the database and phylogenetically analyzed.
Anaplasma capra was detected in blood samples derived from Korean water deer, whereas samples from other animal species were negative. The overall infection rate in tested samples was 13.8% (35/253) and in the water deer the rate was 17.8% (35/198), distributed along the study period from 2015 to 2018. Genetic profiling and a phylogenetic analysis based on analyzed gene markers revealed the occurrence of two distinct strains, clustered in a single clade with counterpart sequences of A. capra in the database.
Anaplasma capra infection were detected in Korean water deer in the Republic of Korea, providing insight into the role of wildlife as a potential reservoir for animal and human anaplasmosis. However, further work is needed in order to evaluate the role of Korean water deer as a host/reservoir host of A. capra.
The SH3 and multiple ankyrin repeat domains 3 (Shank3) proteins are core organizers of the postsynaptic density in neuronal excitatory synapses, and their defects cause various neurodevelopmental and ...neuropsychiatric disorders. Mechanistically, Shank3 directly and indirectly interacts with hundreds of synaptic proteins with diverse functions and potentially exerts its regulatory roles in synaptic development and function via these interactors. However, Shank3‐dependent regulation of synaptic abundance has been validated in vivo for only a few Shank3 interactors. Here, using a quantitative proteomic analysis, we identified 136 proteins with altered synaptic abundance in the striatum of Shank3‐overexpressing transgenic (TG) mice. By comparing these proteins with those found in a previous analysis of the postsynaptic density of Shank3 knock‐out (KO) striatum, we identified and confirmed that cylindromatosis‐associated deubiquitinase (Cyld), a deubiquitinase specific for Lys63‐linked polyubiquitin chains, was up‐ and down‐regulated in Shank3 TG and KO striatal synapses, respectively. Consistently, we found that the synaptic levels of Lys63‐linked polyubiquitin chains were down‐ and up‐regulated in the Shank3 TG and KO striata, respectively. Furthermore, by isolating and analyzing the synaptic Cyld complex, we generated a Cyld interactome consisting of 103 proteins, which may include Cyld substrates. Bioinformatic analyses suggested associations of the Cyld interactome with a few brain disorders and synaptic functions. Taken together, these results suggest that Shank3 regulates the synaptic abundance of Cyld in the mouse striatum and, thereby, potentially modulates the Lys63‐linked polyubiquitination of striatal synaptic proteins.
The striatum‐enriched Shank3 proteins are core scaffolds in the postsynaptic compartment, and genetic variants of the SHANK3 are causally associated with numerous brain disorders. Here, we show that Shank3 positively regulates striatal synaptic abundance of Cyld, a deubiquitinase specific for Lys63‐linked polyubiquitin chains. Consistently, the synaptic levels of Lys63‐linked polyubiquitin chains were down‐ and up‐regulated in the striatum of Shank3 overexpressing and knock‐out mice, respectively. Therefore, Shank3 dosage affects Lys63‐linked polyubiquitination of the striatal synaptic proteome via Cyld. We think that this can be a novel mechanism by which Shank3 controls striatal synaptic development and function.
Background
High‐mobility group box 1 (HMGB1) is a key mediator of neuroinflammation and there are increased HMGB1 levels in laboratory animal models of epilepsy and human patients with epilepsy.
...Objectives
To determine serum HMGB1 levels in dogs with epilepsy.
Animals
Twenty‐eight epileptic dogs, 12 dogs with nonepileptic brain diseases, and 26 healthy dogs.
Methods
In this case‐control study, serum HMGB1 concentrations were estimated using the canine‐specific enzyme‐linked immunosorbent assay kit. Diagnosis of dogs with epilepsy was based on medical history, physical and neurological examination findings, laboratory test results, magnetic resonance image, and cerebrospinal fluid analysis.
Results
Serum HMGB1 levels were significantly higher in epileptic dogs (median = 0.41 ng/mL; range, 0.03‐5.28) than in healthy dogs (median = 0.12 ng/mL; range, 0.02‐1.45; P = .002). In contrast, serum HMGB1 levels of dogs with non‐epileptic brain diseases (median = 0.19 ng/mL; range, 0.03‐1.04) were not significantly increased compared to those of healthy dogs (P = .12). Regarding idiopathic epilepsy, dogs with an epilepsy course of >3 months showed a higher serum HMGB1 concentration (median = 0.87 ng/mL; range, 0.42‐2.88) than those with that of ≤3 months (median = 0.26 ng/mL; range, 0.03‐0.88; P = .02).
Conclusions and Clinical Importance
Serum HMGB1 could be a biomarker of epilepsy.
The assessment of postmortem degradation of skeletal muscle proteins has emerged as a novel approach to estimate the time since death in the early to mid-postmortem phase (approximately 24 h ...postmortem (hpm) to 120 hpm). Current protein-based methods are limited to a small number of skeletal muscle proteins, shown to undergo proteolysis after death. In this study, we investigated the usability of a target-based and unbiased system-wide protein analysis to gain further insights into systemic postmortem protein alterations and to identify additional markers for postmortem interval (PMI) delimitation. We performed proteomic profiling to globally analyze postmortem alterations of the rat and mouse skeletal muscle proteome at defined time points (0, 24, 48, 72, and 96 hpm), harnessing a mass spectrometry-based quantitative proteomics approach. Hierarchical clustering analysis for a total of 579 (rat) and 896 (mouse) quantified proteins revealed differentially expressed proteins during the investigated postmortem period. We further focused on two selected proteins (eEF1A2 and GAPDH), which were shown to consistently degrade postmortem in both rat and mouse, suggesting conserved intra- and interspecies degradation behavior, and thus preserved association with the PMI and possible transferability to humans. In turn, we validated the usefulness of these new markers by classical Western blot experiments in a rat model and in human autopsy cases. Our results demonstrate the feasibility of mass spectrometry–based analysis to discover novel protein markers for PMI estimation and show that the proteins eEF1A2 and GAPDH appear to be valuable markers for PMI estimation in humans.
Natural killer T (NKT) cells are unconventional T cells that bridge innate and adaptive immunity. NKT cells have been implicated in the development of atopic dermatitis (AD).
We aimed to investigate ...the role of NKT cells in AD development, especially in skin.
Global proteomic and transcriptomic analyses were performed by using skin and blood from human healthy–controls and patients with AD. Levels of CXCR4 and CXCL12 expression in skin NKT cells were analyzed in human AD and mouse AD models. By using parabiosis and intravital imaging, the role of skin CXCR4+ NKT cells was further evaluated in models of mice with AD by using CXCR4–conditionally deficient or CXCL12 transgenic mice.
CXCR4 and its cognate ligand CXCL12 were significantly upregulated in the skin of humans with AD by global transcriptomic and proteomic analyses. CXCR4+ NKT cells were enriched in AD skin, and their levels were consistently elevated in our models of mice with AD. Allergen-induced NKT cells participate in cutaneous allergic inflammation. Similar to tissue-resident memory T cells, the predominant skin NKT cells were CXCR4+ and CD69+. Skin-resident NKT cells uniquely expressed CXCR4, unlike NKT cells in the liver, spleen, and lymph nodes. Skin fibroblasts were the main source of CXCL12. CXCR4+ NKT cells preferentially trafficked to CXCL12-rich areas, forming an enriched CXCR4+ tissue-resident NKT cells/CXCL12+ cell cluster that developed in acute and chronic allergic inflammation in our models of mice with AD.
CXCR4+ tissue-resident NKT cells may form a niche that contributes to AD, in which CXCL12 is highly expressed.
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The COVID-19 pandemic was caused by the zoonotic SARS-CoV-2. A variety of animals involved in human life worldwide have been investigated for infection. As the degree of infection increased, ...extensive monitoring in animals became necessary to determine the degree of infection in animals. The study was conducted on a sample of dogs and cats, which were randomly sampled according to the number of confirmed cases in the region. Animals from both COVID-19-confirmed households and generally disease-negative families and animal shelters were included. Tests included real-time qPCR tests for SARS-CoV-2 antigens, ELISA for antibodies, and plaque reduction neutralization tests (PRNT) for neutralizing antibodies. As a result, SARS-CoV-2 viral RNA was detected in 2 cats out of 1018 pets (672 dogs and 346 cats). A total of 16 dogs (2.38%) and 18 cats (5.20%) tested positive using ELISA, and 14 dogs (2.08%) and 17 cats (4.91%) tested positive using PRNT. Antigens of- and/or antibodies to SARS-CoV-2 were detected in the animals regardless of whether the companion family was infected; this was the case even in animal shelters, which have been regarded as relatively safe from transmission. In conclusion, continuous viral circulation between humans and animals is inevitable; therefore, continuous monitoring in animals is required.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Knowledge of the proper dry weight plays a critical role in the efficiency of dialysis and the survival of hemodialysis patients. Recently, bioimpedance spectroscopy(BIS) has been widely used for set ...dry weight in hemodialysis patients. However, BIS is often misrepresented in clinical healthy weight. In this study, we tried to predict the clinically proper dry weight (DWCP) using machine learning for patient's clinical information including BIS. We then analyze the factors that influence the prediction of the clinical dry weight.
As a retrospective, single center study, data of 1672 hemodialysis patients were reviewed. DWCP data were collected when the dry weight was measured using the BIS (DWBIS). The gap between the two (GapDW) was calculated and then grouped and analyzed based on gaps of 1 kg and 2 kg.
Based on the gap between DWBIS and DWCP, 972, 303, and 384 patients were placed in groups with gaps of <1 kg, ≧1kg and <2 kg, and ≧2 kg, respectively. For less than 1 kg and 2 kg of GapDW, It can be seen that the average accuracies for the two groups are 83% and 72%, respectively, in usign XGBoost machine learning. As GapDW increases, it is more difficult to predict the target property. As GapDW increase, the mean values of hemoglobin, total protein, serum albumin, creatinine, phosphorus, potassium, and the fat tissue index tended to decrease. However, the height, total body water, extracellular water (ECW), and ECW to intracellular water ratio tended to increase.
Machine learning made it slightly easier to predict DWCP based on DWBIS under limited conditions and gave better insights into predicting DWCP. Malnutrition-related factors and ECW were important in reflecting the differences between DWBIS and DWCP.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Birds of prey (raptors) are dominant apex predators in terrestrial communities, with hawks (Accipitriformes) and falcons (Falconiformes) hunting by day and owls (Strigiformes) hunting by night.
Here, ...we report new genomes and transcriptomes for 20 species of birds, including 16 species of birds of prey, and high-quality reference genomes for the Eurasian eagle-owl (Bubo bubo), oriental scops owl (Otus sunia), eastern buzzard (Buteo japonicus), and common kestrel (Falco tinnunculus). Our extensive genomic analysis and comparisons with non-raptor genomes identify common molecular signatures that underpin anatomical structure and sensory, muscle, circulatory, and respiratory systems related to a predatory lifestyle. Compared with diurnal birds, owls exhibit striking adaptations to the nocturnal environment, including functional trade-offs in the sensory systems, such as loss of color vision genes and selection for enhancement of nocturnal vision and other sensory systems that are convergent with other nocturnal avian orders. Additionally, we find that a suite of genes associated with vision and circadian rhythm are differentially expressed in blood tissue between nocturnal and diurnal raptors, possibly indicating adaptive expression change during the transition to nocturnality.
Overall, raptor genomes show genomic signatures associated with the origin and maintenance of several specialized physiological and morphological features essential to be apex predators.
Manipulating autophagy is a promising strategy for treating cancer as several autophagy inhibitors are shown to induce autophagic cell death. One of these, autophagonizer (APZ), induces ...apoptosis-independent cell death by binding an unknown target via an unknown mechanism. To identify APZ targets, we used a label-free drug affinity responsive target stability (DARTS) approach with a liquid chromatography/tandem mass spectrometry (LC-MS/MS) readout. Of 35 protein interactors, we identified Hsp70 as a key target protein of unmodified APZ in autophagy. Either APZ treatment or Hsp70 inhibition attenuates integrity of lysosomes, which leads to autophagic cell death exhibiting an excellent synergism with a clinical drug, temozolomide, in vitro, in vivo, and orthotropic glioma xenograft model. These findings demonstrate the potential of APZ to induce autophagic cell death and its development to combinational chemotherapeutic agent for glioma treatment. Collectively, our study demonstrated that APZ, a new autophagy inhibitor, can be used as a potent antitumor drug candidate to get over unassailable glioma and revealed a novel function of Hsp70 in lysosomal integrity regulation of autophagy.
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