Improving immunogenicity and safety of flagellin as vaccine carrier by high-density display on virus-like particle surface

Flagellin is a protein-based adjuvant that activates toll-like receptor (TLR) 5. Flagellin has been actively explored as vaccine adjuvants and carriers. Preclinical and clinical studies find flagellin-based vaccines have a risk to induce systemic adverse reactions potentially due to its overt activation of TLR5. To improve safety and immunogenicity of flagellin as vaccine carriers, FljB was displayed at high densities on hepatitis b core (HBc) virus-like particle (VLP) surface upon c/e1 loop insertion. FljB-HBc (FH) VLPs showed significantly reduced ability to activate TLR5 or induce systemic interleukin-6 release as compared to FljB. FH VLPs also failed to significantly increase rectal temperature of mice, while FljB could significantly increase rectal temperature of mice. These data indicated systemic safety of FljB could be significantly improved by high-density display on HBc VLP surface. Besides improved safety, FH VLPs and FljB similarly boosted co-administered ovalbumin immunization and FH VLPs were found to induce two-fold higher anti-FljB antibody titer than FljB. These data indicated preserved adjuvant potency and improved immunogenicity after high-density display of FljB on HBc VLP surface. Consistent with the high immunogenicity, FH VLPs were found to be more efficiently taken up by bone marrow-derived dendritic cells and stimulate more potent dendritic cell maturation than FljB. Lastly, FH VLPs were found to be a more immunogenic carrier than FljB, HBc VLPs, or the widely used keyhole limpet hemocyanin for nicotine vaccine development with a good local and systemic safety. Our data support FH VLPs to be a potentially safer and more immunogenic carrier than FljB for vaccine development

Transsion TSUP's speech recognition system for ASRU 2023 MADASR Challenge

This paper presents a speech recognition system developed by the Transsion Speech Understanding Processing Team (TSUP) for the ASRU 2023 MADASR Challenge. The system focuses on adapting ASR models for low-resource Indian languages and covers all four tracks of the challenge. For tracks 1 and 2, the acoustic model utilized a squeezeformer encoder and bidirectional transformer decoder with joint CTC-Attention training loss. Additionally, an external KenLM language model was used during TLG beam search decoding. For tracks 3 and 4, pretrained IndicWhisper models were employed and finetuned on both the challenge dataset and publicly available datasets. The whisper beam search decoding was also modified to support an external KenLM language model, which enabled better utilization of the additional text provided by the challenge. The proposed method achieved word error rates (WER) of 24.17%, 24.43%, 15.97%, and 15.97% for Bengali language in the four tracks, and WER of 19.61%, 19.54%, 15.48%, and 15.48% for Bhojpuri language in the four tracks. These results demonstrate the effectiveness of the proposed method

Robust neuroinflammation and perivascular pathology in rTg-DI rats, a novel model of microvascular cerebral amyloid angiopathy

Background Cerebral amyloid angiopathy (CAA) is a common cerebral small vessel disease of the aged and a prominent comorbidity of Alzheimer’s disease (AD). CAA can promote a variety of vascular-related pathologies including neuroinflammation, cerebral infarction, and hemorrhages, which can all contribute to vascular cognitive impairment and dementia (VCID). Our understanding of the pathogenesis of CAA remains limited and further investigation of this condition requires better preclinical animal models that more accurately reflect the human disease. Recently, we generated a novel transgenic rat model for CAA (rTg-DI) that develops robust and progressive microvascular CAA, consistent microhemorrhages and behavioral deficits. Methods In the current study, we investigated perivascular pathological processes that accompany the onset and progressive accumulation of microvascular CAA in this model. Cohorts of rTg-DI rats were aged to 3 months with the onset of CAA and to 12 months with advanced stage disease and then quantitatively analyzed for progression of CAA, perivascular glial activation, inflammatory markers, and perivascular stress. Results The rTg-DI rats developed early-onset and robust accumulation of microvascular amyloid. As the disease progressed, rTg-DI rats exhibited increased numbers of astrocytes and activated microglia which were accompanied by expression of a distinct subset of inflammatory markers, perivascular pericyte degeneration, astrocytic caspase 3 activation, and disruption of neuronal axonal integrity. Conclusions Taken together, these results demonstrate that rTg-DI rats faithfully mimic numerous aspects of human microvascular CAA and provide new experimental insight into the pathogenesis of neuroinflammation and perivascular stress associated with the onset and progression of this condition, suggesting new potential therapeutic targets for this condition. The rTg-DI rats provide an improved preclinical platform for developing new biomarkers and testing therapeutic strategies for microvascular CAA

Velocity Dispersion σaper\sigma_{\rm aper} Aperture Corrections as a Function of Galaxy Properties from Integral-field Stellar Kinematics of 10,000 MaNGA Galaxies

The second moment of the stellar velocity within the effective radius, denoted by $\sigma_{\rm e}^2$, is a crucial quantity in galaxy studies as it provides insight into galaxy properties and their mass distributions. However, large spectroscopic surveys typically do not measure $\sigma_{\rm e}$ directly, instead providing $\sigma_{\rm aper}$, the second moment of the stellar velocity within a fixed fiber aperture. In this paper, we derive an empirical aperture correction formula, given by $\sigma_{\rm aper}/\sigma_{\rm e}=(R_{\rm aper}/R_{\rm e})^{\alpha}$, using spatially resolved stellar kinematics extracted from approximately 10,000 Sloan Digital Sky Survey-Mapping Nearby Galaxies at Apache Point Observatory (SDSS-MaNGA) integral field unit observations. Our analysis reveals a strong dependence of $\alpha$ on the $r$-band absolute magnitude $M_{\rm r}$, $g-i$ color, and Sersic index $n_{\rm Ser}$, where $\alpha$ values are lower for brighter, redder galaxies with higher Sersic indices. Our results demonstrate that the aperture correction derived from previous literature on early-type galaxies cannot be applied to predict the aperture corrections for galaxies with intermediate Sersic indices. We provide a lookup table of $\alpha$ values for different galaxy types, with parameters in the ranges of $-18>M_{\rm r}>-24$, $0.4<g-i<1.6$, and $0<n_{\rm Ser}<8$. A Python script is provided to obtain the correction factors from the lookup table.Comment: 12 pages, 10 figures, 1 table, published in Research in Astronomy and Astrophysic

Reduced Levels of Cerebrospinal Fluid/Plasma Aβ40 as an Early Biomarker for Cerebral Amyloid Angiopathy in RTg-DI Rats

The accumulation of fibrillar amyloid β-protein (Aβ) in blood vessels of the brain, the condition known as cerebral amyloid angiopathy (CAA), is a common small vessel disease that promotes cognitive impairment and is strongly associated with Alzheimer’s disease. Presently, the clinical diagnosis of this condition relies on neuroimaging markers largely associated with cerebral macro/microbleeds. However, these are markers of late-stage disease detected after extensive cerebral vascular amyloid accumulation has become chronic. Recently, we generated a novel transgenic rat model of CAA (rTg-DI) that recapitulates multiple aspects of human CAA disease with the progressive accumulation of cerebral vascular amyloid, largely composed of Aβ40, and the consistent emergence of subsequent microbleeds. Here, we investigated the levels of Aβ40 in the cerebrospinal fluid (CSF) and plasma of rTg-DI rats as CAA progressed from inception to late stage disease. The levels of Aβ40 in CSF and plasma precipitously dropped at the early onset of CAA accumulation at three months of age and continued to decrease with the progression of disease. Notably, the reduction in CSF/plasma Aβ40 levels preceded the emergence of cerebral microbleeds, which first occurred at about six months of age, as detected by in vivo magnetic resonance imaging and histological staining of brain tissue. These findings support the concept that reduced CSF/plasma levels of Aβ40 could serve as a biomarker for early stage CAA disease prior to the onset of cerebral microbleeds for future therapeutic intervention

The rat frontal orienting field dynamically encodes value for economic decisions under risk

Frontal and parietal cortex are implicated in economic decision-making, but their causal roles are untested. Here we silenced the frontal orienting field (FOF) and posterior parietal cortex (PPC) while rats chose between a cued lottery and a small stable surebet. PPC inactivations produced minimal short-lived effects. FOF inactivations reliably reduced lottery choices. A mixed-agent model of choice indicated that silencing the FOF caused a change in the curvature of the rats' utility function (U = Vρ). Consistent with this finding, single-neuron and population analyses of neural activity confirmed that the FOF encodes the lottery value on each trial. A dynamical model, which accounts for electrophysiological and silencing results, suggests that the FOF represents the current lottery value to compare against the remembered surebet value. These results demonstrate that the FOF is a critical node in the neural circuit for the dynamic representation of action values for choice under risk

Expression and characterization of the UL31 protein from duck enteritis virus

<p>Abstract</p> <p>Background</p> <p>Previous studies indicate that the UL31 protein and its homology play similar roles in nuclear egress of all <it>herpesviruses</it>. However, there is no report on the UL31 gene product of DEV. In this study, we expressed and presented the basic properties of the DEV UL31 product.</p> <p>Results</p> <p>The entire ORF of the UL31 was cloned into pET 32a (+) prokaryotic expression vector. <it>Escherichia coli </it>BL21(DE3) competent cells were transformed with the construct followed by the induction of protein expression by the addition of IPTG. Band corresponding to the predicted sizes (55 kDa) was produced on the SDS-PAGE. Over expressed 6×His-UL31 fusion protein was purified by nickel affinity chromatography. The DEV UL31 gene product has been identified by using a rabbit polyclonal antiserum raised against the purified protein. A protein of approximate 35 kDa that reacted with the antiserum was detected in immunoblots of DEV-infected cellular lysates, suggesting that the 35 kDa protein was the primary translation product of the UL31 gene. RT-PCR analyses revealed that the UL31 gene was transcribed most abundantly during the late phase of replication. Subsequently, Immunofluorescence analysis revealed that the protein was widespread speckled structures in the nuclei of infected cells. Western blotting of purified virion preparations showed that UL31 was a component of intracellular virions but was absent from mature extracellular virions. Finally, an Immunofluorescence assay was established to study the distribution of the UL31 antigen in tissues of artificially DEV infected ducks. The results showed that the UL31 antigen was primarily located in the cells of digestive organs and immunological organs.</p> <p>Conclusion</p> <p>In this work, we present the basic properties of the DEV UL31 product. The results indicate that DEV UL31 shares many similarities with its HSV or PRV homolog UL31 and suggest that functional cross-complementation is possible between members of the <it>Alpha</it>herpesvirus subfamily. Furthermore, in vivo experiments with ducks infected with UL31-defective isolates of DEV will also be of importance in order to assess the possible role of the UL31 protein in viral pathogenesis. These properties of the UL31 protein provide a prerequisite for further functional analysis of this gene.</p

Induction of immune responses in ducks with a DNA vaccine encoding duck plague virus glycoprotein C

<p>Abstract</p> <p>Background</p> <p>A DNA vaccine expressing glycoprotein C (gC) of duck plague virus (DPV) was evaluated for inducing immunity in ducks. The plasmid encoding gC of DPV was administered via intramuscular (IM) injection and gene gun bombardment.</p> <p>Results</p> <p>After immunization by both routes virus-specific serum antibody and T-cell responses developed. Vaccination of ducks by IM injection induced a stronger humoral, but weaker cell-mediated immune response. In contrast, a better cell-mediated immune response was achieved by using a gene gun to deliver DNA-coated gold beads to the epidermis with as little as 6 μg of DNA.</p> <p>Conclusions</p> <p>This demonstrated that both routes of DNA inoculation can be used for eliciting virus-specific immune responses. Although DNA vaccine containing DPV gC is effective in both intramuscular injection and gene gun bombardment, the latter could induce significantly higher cell-mediated responses against DPV.</p

Laparoscopic Radical Hysterectomy Results in Higher Recurrence Rate Versus Open Abdominal Surgery for Stage IB1 Cervical Cancer Patients With Tumor Size Less Than 2 Centimeter: A Retrospective Propensity Score-Matched Study

ObjectiveTo compare the oncologic outcomes between laparoscopic and open radical hysterectomy in patients with stage IB1 cervical cancer lesion less than 2 cm.MethodsPatients diagnosed FIGO (2009) stage IB1 (tumor diameter &lt;2 cm) and underwent radical hysterectomy in our hospital between March 2008 and November 2018 were studied. A propensity-matched comparison (1:2) was conducted to minimize selection biases. Demographic and baseline oncologic characteristics were balanced between groups. Overall survival (OS) and disease-free survival (DFS) were assessed using the Kaplan–Meier model, along with univariable and multivariable regression analysis.ResultsA total of 261 patients were enrolled in this study after propensity-matching, with 174 in the open group and 87 in the laparoscopic group. Disease relapsed in seven patients in laparoscopy group, and the recurrence rate was 8.0% (7/87). There were eight patients underwent abdominal radical hysterectomy experienced recurrence, and the recurrence rate was 4.6% (8/174). The multivariate analysis model revealed that laparoscopic operation was associated with higher risk of recurrence than abdominal radical hysterectomy (HR, 3.789; 95% CI, 1.143–12.559; p = 0.029). There were five patients or 2.9% (5/174) died in open surgery group and the corresponding percentage in laparoscopy group was 2.3% (2/87). No difference was found in OS between the two groups (HR, 1.823; 95% CI, 0.2673–12.44; log-rank p = 0.5398). All the recurrence occurred within two years after operation in the laparoscopy group, among which pelvic recurrence (85.7%) was dominant.ConclusionTraditional laparotomy radical hysterectomy has a lower recurrence rate when compared with laparoscopic operation in those cervical cancer patients with a foci diameter less than 2 cm. However, no detrimental effect on survival was found in minimal invasive operation group. Further multi-center prospective trials are needed to confirm our results on a large scale

Characterization of the duck enteritis virus UL55 protein

<p>Abstract</p> <p>Background</p> <p>Characteration of the newly identified duck enteritis virus UL55 gene product has not been reported yet. Knowledge of the protein UL55 can provide useful insights about its function.</p> <p>Results</p> <p>The newly identified duck enteritis virus UL55 gene was about 561 bp, it was amplified and digested for construction of a recombinant plasmid pET32a(+)/UL55 for expression in Escherichia coli. SDS-PAGE analysis revealed the recombinant protein UL55(pUL55) was overexpressed in Escherichia coli BL21 host cells after induction by 0.2 mM IPTG at 37°C for 4 h and aggregated as inclusion bodies. The denatured protein about 40 KDa named pUL55 was purified by washing five times, and used to immune rabbits for preparation of polyclonal antibody. The prepared polyclonal antibody against pUL55 was detected and determined by Agar immundiffusion and Neutralization test. The results of Wstern blotting assay and intracellular analysis revealed that pUL55 was expressed most abundantly during the late phase of replication and mainly distributed in cytoplasm in duck enteritis virus infected cells.</p> <p>Conclusions</p> <p>In this study, the duck enteritis virus UL55 protein was successfully expressed in prokaryotic expression system. Besides, we have prepared the polyclonal antibody against recombinant prtein UL55, and characterized some properties of the duck enteritis virus UL55 protein for the first time. The research will be useful for further functional analysis of this gene.</p