Publications by authors named "Charles Li"

131 Publications

The excretory-secretory antigen HcADRM1 to generate protective immunity against .

Parasitology 2021 Jun 30:1-39. Epub 2021 Jun 30.

MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu210095, P. R. China.

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http://dx.doi.org/10.1017/S0031182021001141DOI Listing
June 2021

Implementation of emergent MRI for wake-up stroke: a single-center experience.

Emerg Radiol 2021 Jun 30. Epub 2021 Jun 30.

Division of Neuroradiology, Imaging Institute, Allegheny Health Network, 320 E. North Ave, Pittsburgh, PA, USA.

Purpose: Recent updates in national guidelines for management of acute ischemic stroke in patients of unknown time of symptom onset ("wake-up" strokes) incorporate, for the first time, use of emergent MRI. In this retrospective case series, we analyze our experience at a Comprehensive Stroke Center implementing a new workflow including MRI in this clinical setting. This study also describes "DWI-FLAIR" mismatch, a critical concept for the interpretation of emergent brain MRIs performed for wake-up strokes.

Methods: Over a 14-month period, all brain MRIs for wake-up stroke were identified. The imaging was analyzed by two board-certified, fellowship-trained neuroradiologists, and a diagnosis of DWI-FLAIR mismatch was made by consensus. Process metrics assessed included interval between last known well time and brain imaging, interval between CT and MRI, and interval between brain MRI and interpretation.

Results: Sixteen patients with a history of "wake-up stroke" were identified. Thirteen of the 16 patients (81.3%) were found to have a DWI-FLAIR mismatch, suggesting infarct < 4.5 h old. The mean time between last known well and MRI was 7.89 h with mean interval between CT and MRI of 1.83 h. Forty-six percent of patients with DWI-FLAIR mismatch received intravenous thrombolysis.

Conclusion: In this "real world" assessment of incorporation of emergent MRI for wake-up strokes, there were several key factors to successful implementation of this new workflow, including effective and accurate description of MRI findings; close collaboration amongst stakeholders; 24/7 availability of MRI; and 24/7 onsite coverage by neurology and radiology physicians.
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http://dx.doi.org/10.1007/s10140-021-01955-wDOI Listing
June 2021

Ophthalmology and COVID-19: The Impact of the Pandemic on Patient Care and Outcomes-An IRIS® Registry Study.

Ophthalmology 2021 Jun 16. Epub 2021 Jun 16.

Verana Health, San Francisco, California; Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. Electronic address:

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http://dx.doi.org/10.1016/j.ophtha.2021.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213986PMC
June 2021

Clinical Outcomes of Rhegmatogenous Retinal Detachment Treated With Pneumatic Retinopexy.

JAMA Ophthalmol 2021 Jun 17. Epub 2021 Jun 17.

VitreoRetinal Surgery, PA, Minneapolis, Minnesota.

Importance: Pneumatic retinopexy (PR) is the only clinic-based method of rhegmatogenous retinal detachment (RRD) repair. Registry-acquired clinical practice setting outcomes data with this procedure have not yet been reported.

Objective: To describe the clinical outcomes associated with RRD treated primarily with PR.

Design, Setting, And Participants: In this retrospective cohort study, data from patients 19 years and older with noncomplex RRD treated at academic and private ophthalmology practices participating in the American Academy of Ophthalmology IRIS Registry (Intelligent Research in Sight) were analyzed. Data were collected from January 1, 2013, to December 31, 2019, and data were analyzed from January to December 2020.

Exposures: Data from the IRIS Registry were queried for eyes that underwent PR for noncomplex RRD and had at least 3 months of follow-up. Cases were identified by a combination of diagnosis code for RRD and a Current Procedural Terminology code for PR.

Main Outcomes And Measures: The number of eyes that achieved single-operation success (SOS), defined as retinal reattachment without a subsequent retinal detachment surgery or repeated PR.

Results: Of 9553 included patients, 5827 (61.0%) were male, and the mean (SD) age was 62 (10) years. A total of 9659 eyes were identified. SOS was achieved in 6613 eyes (68.5%). Best-corrected visual acuity significantly differed 9 to 12 months after treatment between the SOS group, with a mean of 0.24 logMAR (95% CI, 0.23-0.25; approximate Snellen equivalent, 20/35), and the single-operation failure group, with a mean of 0.43 logMAR (95% CI, 0.40-0.46; approximate Snellen equivalent, 20/54). Among all patients, the mean time to maximal visual recovery was 268 days (95% CI, 260-276). Endophthalmitis was observed in 3 eyes (0.03%). SOS was associated with female sex (odds ratio, 1.51; 95% CI, 1.38-1.65), while current smoking status was associated single-operation failure (odds ratio, 0.78; 95% CI, 0.68-0.91).

Conclusions And Relevance: In this registry-based study, which encompasses a large number of eyes drawn from multiple, heterogenous electronic health record systems, SOS was achieved in 68.5% of eyes with noncomplex RRD treated by primary PR. It is unknown how these outcomes would have compared with other methods of RRD repair in this cohort.
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http://dx.doi.org/10.1001/jamaophthalmol.2021.1860DOI Listing
June 2021

Research Note: First report on the detection of necrotic enteritis (NE) B-like toxin in biological samples from NE-afflicted chickens using capture enzyme-linked immunosorbent assay.

Poult Sci 2021 Jul 20;100(7):101190. Epub 2021 Apr 20.

Southern Poultry Research Group, Inc., 1061 Hale Road, Watkinsville, GA 30677, USA.

Necrotic enteritis (NE) is a devastating enteric disease caused by Clostridium perfringens type G. One of the pore-forming toxins, NE B-like (NetB) toxin, secreted by pathogenic C. perfringens type G, has been proposed to be the main virulent factor in NE pathogenesis. The present study aimed to detect the presence of NetB toxin in biological samples of NE-afflicted chickens using NetB-specific monoclonal-based enzyme-linked immunosorbent assay (ELISA). Biological samples, including serum, digesta, and fecal droppings, were obtained from three previous NE studies (designated as Trials 1 to 3). In Trials 1 and 2, broiler chicks were infected with Eimeria maxima strain 41A on day 1 and followed by the netB-positive C. perfringens on day 18. Serum samples were obtained at 20 d post-hatch (i.e., 2 d post C. perfringens infection). In addition, various samples, including serum, gut digesta, and fecal droppings, that had been collected 0, 6, 24, and 30 h post C. perfringens infection were obtained. In Trial 3, broiler chicks were indirectly infected with litter-contaminated E. maxima on d 14 and followed by netB-positive C. perfringens via drinking water on days 18, 19, and 20. Serum samples and fecal droppings were obtained 21 d post-hatch (i.e., 1 d post last C. perfringens infection). The results showed that NetB toxin was not detected in serum samples in Trials 1 and 3. No NetB toxin was detected in all samples obtained before C. perfringens infection in Trial 2. Low but detectable amounts of NetB toxin were found in the serum samples obtained 6 h post C. perfringens infection in Trial 2. While NetB toxin in digesta and fecal droppings was detected 6 h post C. perfringens infection, its level plateaued 24 and 30 h post C. perfringens infection. In Trial 3, NetB toxin was detected in fecal droppings from the NE group, and its concentration ranged from 2.9 to 3.1 ng/g of wet feces. In Trial 2, NE-specific lesions were not seen 0 and 6 h post C. perfringens infection but exhibited lesions were moderate to severe 24 h post infection, leading to a moderate association (r = +0.527) between NE lesions and NetB toxin in the gut digesta. This is the first study to use NetB-specific monoclonal-based capture ELISA to determine and report the presence of native NetB toxin in biological samples from NE-induced chickens.
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http://dx.doi.org/10.1016/j.psj.2021.101190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182422PMC
July 2021

Positive predictive value and stroke workflow outcomes using automated vessel density (RAPID-CTA) in stroke patients: One year experience.

Neuroradiol J 2021 Apr 28:19714009211012353. Epub 2021 Apr 28.

Department of Radiology, Allegheny Health Network, USA.

Purpose: Several new techniques have emerged for detecting anterior circulation large vessel occlusion by quantifying relative vessel density including RAPID-CTA, potentially allowing for faster triage and decreased time to mechanical thrombectomy. We present our one-year experience on positive predictive value of RAPID-CTA for the detection of large vessel occlusion in patients presenting with stroke symptoms and its effect on treatment time and clinical outcomes.

Materials And Methods: Three hundred and ten patients presenting with stroke symptoms with relative vessel density <60% on RAPID-CTA were included (average age 70 years, 145 male, 165 female). Examinations were considered positive if there was evidence of large vessel occlusion or high grade stenosis. Computed tomography angiography to groin puncture time was calculated during one-year time intervals before and after RAPID-CTA installation. Ninety-day Modified Rankin Scale scores were obtained for patients in each cohort.

Results: Of the 310 patients, 270 had large vessel occlusion or high grade stenosis (87% positive predictive value), with 161 having large vessel occlusion. Using 45% relative vessel density threshold, 129/161 large vessel occlusion were detected (80% sensitivity) and 163/172 examinations were positive (95% positive predictive value). Computed tomography angiography to groin puncture time was significantly lower after deployment of RAPID-CTA (93 min vs 68 min, <0.05). Average 90 day modified Rankin Scale score was lower in the RAPID-CTA group with a higher percentage of patients with functional independence, although the data was not statistically significant.

Conclusion: RAPID-CTA had high positive predictive value for large vessel occlusion with a 45% relative vessel density threshold, which could facilitate active worklist reprioritization. Time to treatment was significantly lower and clinical outcomes were improved after deployment of RAPID-CTA.
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http://dx.doi.org/10.1177/19714009211012353DOI Listing
April 2021

Use of Bevacizumab Injections in Medicare Fee For Service in the IRIS® Registry (Intelligent Research in Sight).

Ophthalmol Retina 2021 Mar 6. Epub 2021 Mar 6.

American Academy of Ophthalmology, San Francisco, California; Oakland University William Beaumont School of Medicine, Rochester, Michigan.

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http://dx.doi.org/10.1016/j.oret.2021.03.003DOI Listing
March 2021

Auditory aversion in absolute pitch possessors.

Cortex 2021 02 5;135:285-297. Epub 2020 Dec 5.

Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.

Absolute pitch (AP) refers to the ability of identifying the pitch of a given tone without reliance on any reference pitch. The downside of possessing AP may be the experience of disturbance when exposed to out-of-tune tones. Here, we investigated this so-far unexplored phenomenon in AP, which we refer to as auditory aversion. Electroencephalography (EEG) was recorded in a sample of AP possessors and matched control musicians without AP while letting them perform a task underlying a so-called affective priming paradigm: Participants judged valenced pictures preceded by musical primes as quickly and accurately as possible. The primes were bimodal, presented as tones in combination with visual notations that either matched or mismatched the actually presented tone. Both samples performed better in judging unpleasant pictures over pleasant ones. In comparison with the control musicians, the AP possessors revealed a more profound discrepancy between the two valence conditions, and their EEG revealed later peaks at around 200 ms (P200) after prime onset. Their performance dropped when responding to pleasant pictures preceded by incongruent primes, especially when mistuned by one semitone. This interference was also reflected in an EEG deflection at around 400 ms (N400) after picture onset, preceding the behavior responses. These findings suggest that AP possessors process mistuned musical stimuli and pleasant pictures as affectively unrelated with each other, supporting an aversion towards out-of-tune tones in AP possessors. The longer prime-related P200 latencies exhibited by AP possessors suggest a delay in integrating musical stimuli, underlying an altered affinity towards pitch-label associations.
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http://dx.doi.org/10.1016/j.cortex.2020.11.020DOI Listing
February 2021

Protection studies of an excretory-secretory protein HcABHD against Haemonchus contortus infection.

Vet Res 2021 Jan 6;52(1). Epub 2021 Jan 6.

MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, P. R. China.

Unlike the successful immunization of native H. contortus antigens that contributed to the realization of the first commercial vaccine Barbervax, not many studies revealed the encouraging protective efficacies of recombinant H. contortus antigens in laboratory trials or under field conditions. In our preliminary study, H. contortus α/β-hydrolase domain protein (HcABHD) was demonstrated to be an immunomodulatory excretory-secretory (ES) protein that interacts with goat T cells. We herein evaluated the protective capacities of two HcABHD preparations, recombinant HcABHD (rHcABHD) antigen and anti-rHcABHD IgG, against H. contortus challenge via active and passive immunization trials, respectively. Parasitological parameter, antibody responses, hematological pathology and cytokine profiling in unchallenged and challenged goats were monitored and determined throughout both trials. Subcutaneous administration of rHcABHD with Freund adjuvants elicited protective immune responses in challenged goats, diminishing cumulative fecal egg counts (FEC) and total worm burden by 54.0% and 74.2%, respectively, whereas passive immunization with anti-rHcABHD IgG conferred substantial protection to challenged goats by generating a 51.5% reduction of cumulative FEC and a 73.8% reduction of total worm burden. Additionally, comparable changes of mucosal IgA levels, circulating IgG levels, hemoglobin levels, and serum interleukin (IL)-4 and IL-17A levels were observed in rHcABHD protein/anti-rHcABHD IgG immunized goats in both trials. Taken together, the recombinant version of HcABHD might have further application under field conditions in protecting goats against H. contortus infection, and the integrated immunological pipeline of ES antigen identification, screening and characterization may provide new clues for further development of recombinant subunit vaccines to control H. contortus.
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http://dx.doi.org/10.1186/s13567-020-00871-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786147PMC
January 2021

A grahame triple-layer model unifies mica monovalent ion exchange, zeta potential, and surface forces.

Adv Colloid Interface Sci 2021 Feb 3;288:102335. Epub 2020 Dec 3.

Chemical and Biomolecular Engineering Department, University of California, Berkeley, CA 94720, United States of America. Electronic address:

A triple-layer model of the mica/water electrical double layer (EDL) unifies prediction of zeta potential, ion-exchange, and surface-force isotherms. The theory treats cations as partially dehydrated and complexed specifically to the anionic exchange sites of mica. A diffuse layer commencing at the outer Helmholtz plane (OHP) balances the surface charge not neutralized by adsorbed cations in the inner Helmholtz plane (IHP). Ion-binding equilibrium constants are assessed from zeta-potential measurements and used thereafter to predict ion-exchange isotherms and surface forces. Basal-plane mica surface charge is almost completely neutralized by specific binding of cations, including hydronium ions. The charge in the diffuse layer is only a few percent of the mica crystallographic charge density but leads to long-range electrostatic interactions between charged surfaces. The Grahame triple-layer model of the aqueous EDL provides a robust, quantitative, and unified description of the mica/water interface.
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http://dx.doi.org/10.1016/j.cis.2020.102335DOI Listing
February 2021

Detection of Necrotic Enteritis B-like Toxin Secreted by Clostridium perfringens Using Capture Enzyme-Linked Immunosorbent Assay.

Avian Dis 2020 12;64(4):490-495

Animal Biosciences and Biotechnology Laboratory, USDA-ARS, 10300 Baltimore Avenue, Beltsville, MD 20705.

Necrotic enteritis (NE) is a devastating enteric disease caused by Clostridium perfringens type A/G, which affects global poultry industry by compromising the performance, health, and welfare of chickens. The causative main virulent factor responsible for NE pathogenesis has been shifted from a phospholipase C portion of an α-toxin, to an NE B-like (NetB) toxin, a plasmid-encoded pore-forming heptameric protein, in NE development. Therefore, the ability to detect NetB toxin will enable early diagnosis of field NE. Because the NetB protein can only be detected by western blot analysis with polyclonal anti-NetB antiserum, we developed a NetB-specific monoclonal antibody (mAb)-based capture enzyme-linked immunosorbent assay (ELISA). Twenty mAbs reacting with Escherichia coli-expressed NetB protein were selected, isotyped, and conjugated with horseradish peroxidase for antibody pair tests. Multiple mAb pairs were found to detect E. coli NetB protein and native NetB protein secreted by netB-positive C. perfringens isolates. The developed capture (sandwich) ELISA could be useful to identify in vitro production of native NetB protein secreted from netB-positive field C. perfringens isolates and to conduct a large field test of commercial chickens undergoing NE infection. Here, we first report that native NetB toxin can be detected in C. perfringens NetB-specific mAb-based capture ELISA.
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http://dx.doi.org/10.1637/0005-2086-64.4.490DOI Listing
December 2020

Escalating Mean Arterial Pressure in Severe Traumatic Brain Injury: A Prospective, Observational Study.

J Neurotrauma 2021 Jul 29;38(14):1995-2002. Epub 2021 Jan 29.

Neurosurgery Department, Alfred Hospital, Melbourne, Victoria, Australia.

To investigate cerebral autoregulatory status in patients with severe traumatic brain injury (TBI), guidelines now suggest active manipulation of mean arterial pressure (MAP). There is a paucity of data, however, describing the effect on intracranial pressure (ICP) when MAP is raised. Consecutive patients with TBI requiring ICP monitoring were enrolled from November 2019 to April 2020. The MAP and ICP were recorded continuously, and clinical annotations were made whenever intravenous vasopressors were commenced or adjusted to defend cerebral perfusion pressure (CPP) targets. A significant change in MAP burden was defined as MAP >100min.mm Hg over 15 min. The primary outcome was the change in ICP burden over the same 15-min period. Bedside and clinical parameters were then compared between these groups. Twenty-eight patients were enrolled, providing 212 clinical events, of which 60 were deemed significant. Over the first 15 min, 65% were associated with a net negative ICP burden. A greater reduction in ICP burden was observed with events occurring in patients without a history of hypotension at scene ( = 0.016), after three days post-injury ( = 0.0018), and where the pressure-reactivity index (PRx) was <0.25 ( = 0.0005) or the ICP amplitude to CPP correlation coefficient (RAC) was <-0.10 ( = 0.0036) at the initiation of vasopressor changes. The ICP burden in the first 15 min was highly correlated with the next 15-min period. In patients with severe TBI requiring ICP monitoring, increasing MAP to pursue a CPP target was followed by a net negative ICP burden in approximately two-thirds of events. These data suggest a MAP challenge may be a useful adjunct in managing intracranial hypertension.
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http://dx.doi.org/10.1089/neu.2020.7289DOI Listing
July 2021

The DIOS framework for optimizing infectious disease surveillance: Numerical methods for simulation and multi-objective optimization of surveillance network architectures.

PLoS Comput Biol 2020 12 4;16(12):e1008477. Epub 2020 Dec 4.

Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, California, United States of America.

Infectious disease surveillance systems provide vital data for guiding disease prevention and control policies, yet the formalization of methods to optimize surveillance networks has largely been overlooked. Decisions surrounding surveillance design parameters-such as the number and placement of surveillance sites, target populations, and case definitions-are often determined by expert opinion or deference to operational considerations, without formal analysis of the influence of design parameters on surveillance objectives. Here we propose a simulation framework to guide evidence-based surveillance network design to better achieve specific surveillance goals with limited resources. We define evidence-based surveillance design as an optimization problem, acknowledging the many operational constraints under which surveillance systems operate, the many dimensions of surveillance system design, the multiple and competing goals of surveillance, and the complex and dynamic nature of disease systems. We describe an analytical framework-the Disease Surveillance Informatics Optimization and Simulation (DIOS) framework-for the identification of optimal surveillance designs through mathematical representations of disease and surveillance processes, definition of objective functions, and numerical optimization. We then apply the framework to the problem of selecting candidate sites to expand an existing surveillance network under alternative objectives of: (1) improving spatial prediction of disease prevalence at unmonitored sites; or (2) estimating the observed effect of a risk factor on disease. Results of this demonstration illustrate how optimal designs are sensitive to both surveillance goals and the underlying spatial pattern of the target disease. The findings affirm the value of designing surveillance systems through quantitative and adaptive analysis of network characteristics and performance. The framework can be applied to the design of surveillance systems tailored to setting-specific disease transmission dynamics and surveillance needs, and can yield improved understanding of tradeoffs between network architectures.
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http://dx.doi.org/10.1371/journal.pcbi.1008477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744064PMC
December 2020

Changes in Social Media Impact of the Radiological Literature During the Covid-19 Pandemic.

Acad Radiol 2021 02 21;28(2):151-157. Epub 2020 Nov 21.

Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, California.

Purpose: The objective of this study was to determine how the social media impact of the radiological literature has changed during the Covid-19 pandemic.

Methods: Altmetric Attention scores were collected for all articles in five leading radiology journals over a 5-year period ending in June 2020, and temporal smoothing yielded the filtered Altmetric Attention (fAA) score. Natural language processing methods were used to label articles with major topic areas. A forecasting model was used to identify periods of outlier behavior in the fAA score aggregated across all journals, for each journal individually, and stratified by article topic area. The distributions of fAA scores prior to the onset of the pandemic were statistically compared to those during the pandemic. For journals exhibiting increased fAA scores, the frequency distributions of articles not related to Covid-19 was compared to that prior to the pandemic.

Results: During the pandemic, we found sustained outliers and statistically significant increases in the aggregate fAA score across all five journals, as well as for Radiology, American Journal of Roentgenology, and Academic Radiology individually. Articles related to Covid-19, thoracic imaging, and radiology education also experienced significantly increased fAA scores during the pandemic period. We did not find significantly decreased rates of publication of non-Covid articles in the journals experiencing elevated fAA scores.

Conclusion: Social media engagement with the radiological literature significantly increased during the Covid-19 pandemic. This preferentially affected certain journals and articles addressing specific topics, reflecting the intense public interest in the diagnosis and treatment of Covid-19.
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http://dx.doi.org/10.1016/j.acra.2020.11.002DOI Listing
February 2021

Comparison of the Pathogenicity of Five Clostridium perfringens Isolates Using an Eimeria maxima Coinfection Necrotic Enteritis Disease Model in Commercial Broiler Chickens.

Avian Dis 2020 09;64(3):386-392

Animal Bioscience and Biotechnology Laboratory, Agricultural Research Service (ARS), United States Department of Agriculture (USDA), Beltsville, MD 20705.

Clostridium perfringens (CP) is the etiologic agent of necrotic enteritis (NE) in broiler chickens that is responsible for massive economic losses in the poultry industry in response to voluntary reduction and withdrawal of antibiotic growth promoters. Large variations exist in the CP isolates in inducing intestinal NE lesions. However, limited information is available on CP isolate genetics in inducing NE with other predisposing factors. This study investigated the ability of five CP isolates from different sources to influence NE pathogenesis by using an Eimeria maxima (EM) coinfection NE model: Str.13 (from soil), LLY_N11 (healthy chicken intestine), SM101 (food poisoning), Del1 (netB+tpeL-) and LLY_Tpel17 (netB+tpeL+) for NE-afflicted chickens. The 2-wk-old broiler chickens were preinfected with EM (5 × 103 oocysts) followed by CP infection (around 1 × 109 colony-forming units per chicken). The group of the LLY_Tpel17 isolate with EM coinfection had 25% mortality. No mortality was observed in the groups infected with EM alone, all CP alone, or dual infections of EM/other CP isolates. In this model of EM/CP coinfections, the relative percentages of body weight gain showed statistically significant decreases in all EM/CP groups except the EM/SM101 group when compared with the sham control group. Evident gut lesions were only observed in the three groups of EM/LLY_N11, EM/Del1, and EM/LLY_Tpel17, all of which possessed an essential NE pathogenesis locus in their genomes. Our studies indicate that LLY_Tpel17 is highly pathogenic to induce severe gut lesions and would be a good CP challenge strain for studies investigating pathogenesis and evaluating the protection efficacy for antibiotic alternative approaches.
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http://dx.doi.org/10.1637/aviandiseases-D-19-00098DOI Listing
September 2020

HcFAR, a functional inhibitor of goat TGF-β1 identified from excretory and secretory products of Haemonchus contortus.

Vet Parasitol 2020 Oct 7;286:109236. Epub 2020 Sep 7.

MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China. Electronic address:

Haemonchus contortus has developed complexed and multifaceted mechanisms of immune evasion to enable the survival in the host. Generating excretion and secretion products (ESPs) to subvert or suppress the functions of host cytokines is a newly immune regulatory pattern found during recent years. Transforming growth factor-β (TGF-β) has critical immune regulatory functions in nematode infections. In this study, co-immunoprecipitation (co-IP) assay was used to identify the goat TGF-β1 binding proteins from HcESPs. The interaction between TGF-β1 and nematode fatty acid retinoid binding domain containing protein of H. contortus (HcFAR) was analyzed by glutathione S-transferase (GST)-pull down assay. The suppressive effect of rHcFAR on TGF-β1-induced immunoglobulin A (IgA) secretion was observed by co-incubation of rHcFAR and TGF-β1 with goat peripheral blood mononuclear cells (PBMCs). The IgA concentrations were determined using enzyme linked immunosorbent assay (ELISA) kit. Meanwhile, the suppressive effect of rHcFAR on TGF-β1-induced T helper (Th) 9 differentiation was investigated by co-incubation of rHcFAR, TGF-β1 and interleukin (IL)-4 with goats PBMCs. In parallel, IL-4 was replaced by IL-6 to determine the effects on the Th17 differentiation. The transcriptions of IL-9 and IL-17 in PBMCs were then evaluated by real-time PCR. Finally, we found that HcFAR from HcESPs could bind to goat TGF-β1 in vitro. The ELISA results of IgA showed that 40 μg/mL rHcFAR could suppress the IgA secretion of PBMCs induced by TGF-β1. Additionally, rHcFAR (at 10 μg/mL and 20 μg/mL) could inhibit the mRNA transcription of IL-9 induced by TGF-β1 and IL-4. Meanwhile, rHcFAR could also downregulate the transcription of IL-17 induced by TGF-β1 and IL-6 in a dose-dependent manner. These results indicated that HcFAR was a functional inhibitor of goat TGF-β1 and this information may help contribute to understanding of the relationship between the ESPs and host cytokines.
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http://dx.doi.org/10.1016/j.vetpar.2020.109236DOI Listing
October 2020

Unveiling the immunomodulatory properties of Haemonchus contortus adhesion regulating molecule 1 interacting with goat T cells.

Parasit Vectors 2020 Aug 18;13(1):424. Epub 2020 Aug 18.

MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China.

Background: Gastrointestinal nematodes could release excretory-secretory (ES) proteins into the host environment to ensure their survival. These ES proteins act as immunomodulators to suppress or subvert the host immune response via the impairment of immune cell functions, especially in chronic infections. In our preliminary study, Haemonchus contortus adhesion-regulating molecule 1 (HcADRM1) was identified from H. contortus ES proteins (HcESPs) that interacted with host T cells via liquid chromatography-tandem mass spectrometry analysis. However, little is known about HcADRM1 as an ES protein which may play a pivotal role at the parasite-host interface.

Methods: Based on bioinformatics approaches, multiple amino acid sequence alignment was conducted and the evolutionary relationship of HcADRM1 with ADRM1 orthologues was extrapolated. Employing RT-qPCR and immunohistochemistry assays, temporal transcriptional and spatial expression profiles of HcADRM1 were investigated. Using immunostaining approaches integrated with immunological bioassays, the immunomodulatory potentials of HcADRM1 on goat T cells were assessed.

Results: We hereby demonstrated that HcADRM1 with immunodiagnostic utility was a mammalian ADRM1 orthologue abundantly expressed at all developmental stages of H. contortus. Given the implications of ADRM1 proteins in cell growth, survival and development, we further investigated the immunomodulatory property of HcADRM1 as an individual ES protein acting at the parasite-host interface. The rHcADRM1 stimuli notably suppressed T cell viability, promoted intrinsic and extrinsic T cell apoptosis, inhibited T cell proliferation and induced cell cycle arrest at G1 phase. Simultaneously, rHcADRM1 stimuli exerted critical controls on T cell cytokine secretion profiles, predominantly by restraining the secretions of interleukin (IL)-4, IL-10 and interferon-gamma.

Conclusions: Importantly, HcADRM1 protein may have prophylactic potential for anti-H. contortus vaccine development. Together, these findings may contribute to the clarification of molecular and immunomodulatory traits of ES proteins, as well as improvement of our understanding of parasite immune evasion mechanism in H. contortus-host biology.
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http://dx.doi.org/10.1186/s13071-020-04297-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432459PMC
August 2020

MeCP2 links heterochromatin condensates and neurodevelopmental disease.

Nature 2020 10 22;586(7829):440-444. Epub 2020 Jul 22.

Whitehead Institute for Biomedical Research, Cambridge, MA, USA.

Methyl CpG binding protein 2 (MeCP2) is a key component of constitutive heterochromatin, which is crucial for chromosome maintenance and transcriptional silencing. Mutations in the MECP2 gene cause the progressive neurodevelopmental disorder Rett syndrome, which is associated with severe mental disability and autism-like symptoms that affect girls during early childhood. Although previously thought to be a dense and relatively static structure, heterochromatin is now understood to exhibit properties consistent with a liquid-like condensate. Here we show that MeCP2 is a dynamic component of heterochromatin condensates in cells, and is stimulated by DNA to form liquid-like condensates. MeCP2 contains several domains that contribute to the formation of condensates, and mutations in MECP2 that lead to Rett syndrome disrupt the ability of MeCP2 to form condensates. Condensates formed by MeCP2 selectively incorporate and concentrate heterochromatin cofactors rather than components of euchromatic transcriptionally active condensates. We propose that MeCP2 enhances the separation of heterochromatin and euchromatin through its condensate partitioning properties, and that disruption of condensates may be a common consequence of mutations in MeCP2 that cause Rett syndrome.
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http://dx.doi.org/10.1038/s41586-020-2574-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735819PMC
October 2020

A Novel α/β Hydrolase Domain Protein Derived From Acts at the Parasite-Host Interface.

Front Immunol 2020 30;11:1388. Epub 2020 Jun 30.

MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China.

The α/β-hydrolase domain (ABHD) proteins belonging to α/β-hydrolase (ABH) superfamily are ubiquitously distributed throughout all the organisms, and their functional roles have been implicated in energy metabolism, cell signaling, growth and development. In our preliminary work, we identified a novel ABHD protein derived from excretory-secretory (ES) proteins (HcESPs) that interacted with host T cells. Here, we demonstrated that ABHD (HcABHD) protein, expressed in all life-cycle stages of , is a mammalian ABHD17 homolog with immunodiagnostic utility and lipase activity. Given its catalytic activities and immunomodulatory potentials, we further investigated the functional diversity of HcABHD as an individual ES protein in parasite-host interactions. HcABHD protein may serve as depalmitoylase or thioesterase to suppress cell viability, inhibit cell proliferation, induce intrinsic and extrinsic T cell apoptosis, and cause cell cycle arrested at G1 phase. Moreover, recombinant HcABHD stimuli exerted critical controls on T cell cytokine production profiles, predominantly by inhibiting the secretions of interleukin (IL)-4, interferon-gamma (IFN-γ) and transforming growth factor-beta (TGF-β) 1, and promoting IL-10 production. As the immunomodulator acting at the parasite-host interface, HcABHD protein may have potential applications for the vaccine development of therapeutic intervention. Together, these findings may help illuminate the molecular and particularly immunomodulatory aspects of ES proteins and contribute to an enhanced understanding of parasite immune evasion in -host biology.
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http://dx.doi.org/10.3389/fimmu.2020.01388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338770PMC
April 2021

Development and characterization of novel mouse monoclonal antibodies against chicken chemokine CC motif ligand 4.

Vet Immunol Immunopathol 2020 Sep 10;227:110091. Epub 2020 Jul 10.

Animal Biosciences and Biotechnology Laboratory, Beltsville Agricultural Research Center, Agricultural Research Service, U.S. Department of Agriculture Beltsville, MD, 20705, USA. Electronic address:

Chemokine (C-C motif) ligand (CCL) 4 is a CC chemokine subfamily member defined by the sequential positioning of conserved cysteine residues. Upon the binding of G-protein-coupled receptors on the cell surface, CCL4 mediates a diverse set of biological processes including chemotaxis, tumorigenesis, homeostasis and thymopoiesis. Although the physiological roles of mammalian CCL4s were elucidated >20 years ago, there is limited information on the biological activities of chicken CCL4 (chCCL4). In the present study, we developed and characterized mouse monoclonal antibodies (mAbs) against chCCL4 to characterize better the immunological properties of chCCL4. Out of initial screening of >400 clones, two mAbs detecting chCCL4, 1A12 and 15D9, were identified and characterized using western blotting and chCCL4-specific antigen-capture enzyme-linked immunosorbent assay, and their neutralizing activity was validated by chCCL4-induced peripheral blood mononuclear cell chemotaxis assay. Furthermore, the intracellular expression of chCCL4 in various chicken cells by immunocytochemistry and flow cytometry was confirmed using 1A12 and 15D9 mAbs. These results collectively indicate that 1A12 and 15D9 mAbs specifically detect chicken CCL4 and they will be valuable immune reagents for basic and applied studies in avian immunology.
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http://dx.doi.org/10.1016/j.vetimm.2020.110091DOI Listing
September 2020

Identification of enterobacteria in viscera of pigs afflicted with porcine reproductive and respiratory syndrome and other viral co-infections.

Microb Pathog 2020 Oct 11;147:104385. Epub 2020 Jul 11.

Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, 330045, China. Electronic address:

In order to investigate enterobacteria presence involved in the secondary infections in Porcine Reproductive and Respiratory Syndrome (PRRS) pigs with different viral co-infections, we identified enterobacteria for guiding clinical treatment. Twenty-one diseased pigs were diagnosed with the PRRS virus (PRRSV) and other 7 virus primers by PCR/RT-PCR in the lung and spleen samples. Enterobacteria were isolated using MacConkey agar from 5 visceral samples of PRRS pigs, and identified by 16S rDNA sequencing. PRRSV was positive in 100% of the lung samples and 81.0% of the spleen samples. Seven diseased pigs were diagnosed with only PRRSV infection (33.3%), 7 pigs with PRRSV and 1 or 2 other viruses (33.3%) and 7 pigs with PRRSV and more than 2 types of other viruses (33.3%). PRRSV was more inclined to co-infect pigs with porcine group A rotavirus (PARV) with the co-infection rate of 52.4% (11/21). Approximately 13 types of bacteria were successfully isolated from lung, spleen, liver, kidney and lymph node samples of different PRRS pigs. Enterobacteria were isolated in 100% of lung, liver and lymph samples from pigs infected with PRRSV alone. However, the isolation rates were significantly decreased in the more than 3 viruses co-infection group. Escherichia coli was the most prevalent bacterium, followed by Morganella, Proteus, Shigella, Salmonella, Klebsiella and Aeromonas. Most of the isolated enterobacteria were opportunistic pathogens. Therefore, timely combination with antimicrobial agents is necessary for effective treatment of PRRS-infected pigs.
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http://dx.doi.org/10.1016/j.micpath.2020.104385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352111PMC
October 2020

Artificial Intelligence Needs Clinical Intelligence to Succeed.

JACC Heart Fail 2020 07;8(7):588-591

Robertson Centre for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, Glasgow, United Kingdom.

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http://dx.doi.org/10.1016/j.jchf.2020.06.002DOI Listing
July 2020

Effects of Eimeria maxima and Clostridium perfringens infections on cecal microbial composition and the possible correlation with body weight gain in broiler chickens.

Res Vet Sci 2020 Oct 25;132:142-149. Epub 2020 May 25.

Animal Biosciences and Biotechnology Laboratory, Agricultural Research Service (ARS), US Department of Agriculture (USDA), Beltsville, MD, USA. Electronic address:

With the voluntary and regulatory withdrawal of antibiotic growth promoters from animal feed, coccidiosis and necrotic enteritis (NE) emerge as the top two enteric poultry infectious diseases responsible for major economic loss worldwide. The objective of this study was to investigate the correlation between the cecal microbiota compositions with the growth trait after coccidiosis and NE. In this study, the effects of Eimeria maxima and/or Clostridium perfringens infections on the microbial composition and potential correlation with the body weight gain were investigated in broiler chickens using 16S rRNA gene sequencing. E. maxima and C. perfringens coinfection successfully induced NE with its typical gut lesions and significant reductions in the percentage of relative body weight gain (RBWG%). The NE challenge model did not affect cecal microbial diversity, but influenced the cecal microbial composition. KEGG enzymes in microbiota were significantly altered in abundance following dual infections. Furthermore, significant correlations between cecal microbiota modules and RBWG% were identified in the sham control, E. maxima or C. perfringens infected groups. Understanding of host-microbiota interaction in NE would enhance the development of antibiotics-independent strategies to reduce the harmful effect of NE on the gut microbiota structure, and improve the gut health and poultry production.
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http://dx.doi.org/10.1016/j.rvsc.2020.05.013DOI Listing
October 2020

Partitioning of cancer therapeutics in nuclear condensates.

Science 2020 06;368(6497):1386-1392

Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.

The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to affect the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.
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http://dx.doi.org/10.1126/science.aaz4427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735713PMC
June 2020

Randomised control trial on the optimal duration of non-weight-bearing walking after hallux valgus surgery.

J Orthop Translat 2020 Jul 13;23:61-66. Epub 2020 May 13.

Department of Orthopaedics and Traumatology, Faculty of Medicine, CUHK, Hong Kong.

Introduction: Hallux valgus surgery is one of the most commonly performed operations in Orthopaedics. Multiple surgical techniques have been described including arthrodesis, osteotomies and soft tissue procedures. The endoscopic-assisted distal soft tissue procedure is one of the minimally invasive surgical options with a good long-term outcome. The rehabilitation protocol for this soft tissue procedure consists of 6-weeks of non-weight bearing walking. This prolonged period of non-weight-bearing walking may ensure a good stabilization of the alignment but is difficult for the patient from a social-economical perspective. In addition, earlier mobilisation has other theoretical advantages including less atrophy and better range of motion. The objective of this trial is to investigate the effect of an earlier weight-bearing regime at 2-weeks post-surgery.

Methods: Randomised control trial of patients undergoing the endoscopic-assisted distal soft tissue procedure. Allocation and randomization of subjects were performed immediately after completion of surgery to avoid intra-operative biases. The control group underwent the usual protocol of 6-weeks of non-weight-bearing walking while the intervention group underwent 2-weeks of post-operative non-weight-bearing walking. Foot function was measured using the Foot and Ankle Outcome Score (FAOS) at the baseline, 12-week post-surgery and 26-weeks post-surgery. The hallux valgus angle, 1,2 inter-metatarsal angle and tibial sesamoid position were also measured during those time-points.

Results: A total of 51 participants completed the study, 29 in the control group and 22 in the early weight-bearing group. 1 patient form the early weight-bearing group was complicated with hallux varus requiring revision surgery. All the patients had significantly improved radiological angles and foot function in both the control and early weight-bearing group. At the 12-week time point, the radiological angles were the same for both groups but foot function was significantly better in the early weightbearing group.

Discussion: Early postoperative weight-bearing did not lead to pre-mature implant failures or increased recurrence rates. It actually resulted in fewer symptoms like stiffness, lessened pain, better performance in daily activities and a better quality of life.

Conclusion: Early weight-bearing walking at 2-week after distal soft tissue reconstruction of hallux valgus is not only safe, it may help accelerate the rehabilitation process and allow patients to return their usual life faster. Being a clinical trial, our results are directly translatable to hallux valgus patients. The results of this study show that a shortened non-weight bearing duration after hallux valgus surgery improves foot function at 12 weeks while not affecting recurrence risks.
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http://dx.doi.org/10.1016/j.jot.2020.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256050PMC
July 2020

Molecular targeting of renal cell carcinoma by an oral combination.

Oncogenesis 2020 May 19;9(5):52. Epub 2020 May 19.

Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd., Augusta, GA, 30912, USA.

The 5-year survival rate of patients with metastatic renal cell carcinoma (mRCC) is <12% due to treatment failure. Therapeutic strategies that overcome resistance to modestly effective drugs for mRCC, such as sorafenib (SF), could improve outcome in mRCC patients. SF is terminally biotransformed by UDP-glucuronosyltransferase-1A9 (A9) mediated glucuronidation, which inactivates SF. In a clinical-cohort and the TCGA-dataset, A9 transcript and/or protein levels were highly elevated in RCC specimens and predicted metastasis and overall-survival. This suggested that elevated A9 levels even in primary tumors of patients who eventually develop mRCC could be a mechanism for SF failure. 4-methylumbelliferone (MU), a choleretic and antispasmodic drug, downregulated A9 and inhibited SF-glucuronidation in RCC cells. Low-dose SF and MU combinations inhibited growth, motility, invasion and downregulated an invasive signature in RCC cells, patient-derived tumor explants and/or endothelial-RCC cell co-cultures; however, both agents individually were ineffective. A9 overexpression made RCC cells resistant to the combination, while its downregulation sensitized them to SF treatment alone. The combination inhibited kidney tumor growth, angiogenesis and distant metastasis, with no detectable toxicity; A9-overexpressing tumors were resistant to treatment. With effective primary tumor control and abrogation of metastasis in preclinical models, the low-dose SF and MU combinations could be an effective treatment option for mRCC patients. Broadly, our study highlights how targeting specific mechanisms that cause the failure of "old" modestly effective FDA-approved drugs could improve treatment response with minimal alteration in toxicity profile.
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http://dx.doi.org/10.1038/s41389-020-0233-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237463PMC
May 2020

Proteomic analysis revealed T cell hyporesponsiveness induced by Haemonchus contortus excretory and secretory proteins.

Vet Res 2020 May 13;51(1):65. Epub 2020 May 13.

MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, China.

Haemonchus contortus has evolved highly integrated and sophisticated mechanisms to promote coexistence with hosts. The excretory-secretory (ES) products generated by this parasite contribute to the regulation of the host immune response to facilitate immune evasion and induce chronicity, but the proteins responsible for this process and the exact cellular mechanisms have yet to be defined. In this study, we identified 114 H. contortus ES proteins (HcESPs) interacting with host T cells and 15 T cell binding receptors via co-immunoprecipitation and shotgun liquid chromatography-tandem mass spectrometry analysis. Based on bioinformatics analysis, we demonstrated that HcESPs could inhibit T cell viability, induce cell apoptosis, suppress T cell proliferation and cause cell cycle arrest. Furthermore, the stimulation of HcESPs exerted critical control effects on T cell cytokine production profiles, predominantly promoting the secretion of interleukin (IL)-10, IL-17A and transforming growth factor-β1 and inhibiting IL-2, IL-4 and interferon-γ production. Collectively, these findings may provide insights into the interaction between ES proteins and key host effector cells, enhancing our understanding of the molecular mechanism underlying parasite immune evasion and providing new clues for novel vaccine development.
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http://dx.doi.org/10.1186/s13567-020-00790-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222441PMC
May 2020

Virtual Read-Out: Radiology Education for the 21st Century During the COVID-19 Pandemic.

Acad Radiol 2020 06 1;27(6):872-881. Epub 2020 May 1.

Department of Radiology, Keck School of Medicine of USC, 1520 San Pablo St. Lower Level, Rm1451, Los Angeles, CA 90033. Electronic address:

Technologic advances have resulted in the expansion of web-based conferencing and education. While historically video-conferencing has been used for didactic educational sessions, we present its novel use in virtual radiology read-outs in the face of the COVID-19 pandemic. Knowledge of key aspects of set-up, implementation, and possible pitfalls of video-conferencing technology in the application of virtual read-outs can help to improve the educational experience of radiology trainees and promote potential future distance learning and collaboration.
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http://dx.doi.org/10.1016/j.acra.2020.04.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252195PMC
June 2020

Haemonchus contortus transthyretin domain - containing protein (HcTTR): A promising vaccine candidate against Haemonchus contortus infection.

Vet Parasitol 2020 Mar 5;279:109045. Epub 2020 Feb 5.

MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China. Electronic address:

Haemonchus contortus transthyretin domain-containing protein (HcTTR) with 136 amino acids belongs to a transthyretin-like (TTL) family member. In our previous study, it was reported that HcTTR was a novel antagonist of the goat cytokine Interleukin 4 (IL-4), and was involved in the regulation of host immune responses, implying that it might be applied for therapeutic strategies or vaccine development against the infection of H. contortus. Thus, the protective capacities of HcTTR against H. contortus infections via active and passive immunization trials were examined. For the passive protection trials, H. contortus-infected goats were intravenously immunized twice with 5 mg of total IgG containing anti-rHcTTR goat polyclonal antibodies. The results showed that the significant rates of reduction in egg shedding and worm burden was 58.12% and 64.61%, respectively, as compared with the positive control group. For the active protection trials, local goats were vaccinated twice with 500 μg of recombinant HcTTR to generate antigen-specific circulating antibodies, resulting in 63.7% reduction in eggs shedding and 66.4% reduction in worm burdens after H. contortus challenge. In both passive and active trials, the immunized goats displayed higher mucosal IgA levels and less anaemic compared to the challenged positive controls. Pen trials indicated that HcTTR generated partial immune protective effects against H. contortus challenge and it could be a promising vaccine candidate for development of effective strategy to control H. contortus.
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http://dx.doi.org/10.1016/j.vetpar.2020.109045DOI Listing
March 2020
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