An Updated Search of Steady TeV γ−\gamma-Ray Point Sources in Northern Hemisphere Using the Tibet Air Shower Array

Using the data taken from Tibet II High Density (HD) Array (1997 February-1999 September) and Tibet-III array (1999 November-2005 November), our previous northern sky survey for TeV $\gamma-$ray point sources has now been updated by a factor of 2.8 improved statistics. From $0.0^{\circ}$ to $60.0^{\circ}$ in declination (Dec) range, no new TeV $\gamma-$ray point sources with sufficiently high significance were identified while the well-known Crab Nebula and Mrk421 remain to be the brightest TeV $\gamma-$ray sources within the field of view of the Tibet air shower array. Based on the currently available data and at the 90% confidence level (C.L.), the flux upper limits for different power law index assumption are re-derived, which are approximately improved by 1.7 times as compared with our previous reported limits.Comment: This paper has been accepted by hepn

Targeted Overexpression of α-Synuclein by rAAV2/1 Vectors Induces Progressive Nigrostriatal Degeneration and Increases Vulnerability to MPTP in Mouse

<div><p>Mutations, duplication and triplication of <i>α-synuclein</i> genes are linked to familial Parkinson’s disease (PD), and aggregation of α-synuclein (α-syn) in Lewy bodies (LB) is involved in the pathogenesis of the disease. The targeted overexpression of α-syn in the substantia nigra (SN) mediated by viral vectors may provide a better alternative to recapitulate the neurodegenerative features of PD. Therefore, we overexpressed human wild-type α-syn using rAAV2/1 vectors in the bilateral SN of mouse and examined the effects for up to 12 weeks. Delivery of rAAV-2/1-α-syn caused significant nigrostriatal degeneration including appearance of dystrophic striatal neurites, loss of nigral dopaminergic (DA) neurons and dissolving nigral neuron bodies in a time-dependent manner. In addition, the α-syn overexpressed mice also developed significant deficits in motor function at 12 weeks when the loss of DA neurons exceeded a threshold of 50%. To investigate the sensitivity to neurotoxins in mice overexpressing α-syn, we performed an MPTP treatment with the subacute regimen 8 weeks after rAAV injection. The impact of the combined genetic and environmental insults on DA neuronal loss, striatal dopamine depletion, dopamine turnover and motor dysfunction was markedly greater than that of either alone. Moreover, we observed increased phosphorylation (S129), accumulation and nuclear distribution of α-syn after the combined insults. In summary, these results reveal that the overexpressed α-syn induces progressive nigrostriatal degeneration and increases the susceptibility of DA neurons to MPTP. Therefore, the targeted overexpression of α-syn and the combination with environmental toxins may provide valuable models for understanding PD pathogenesis and developing related therapies.</p></div

High normal alanine aminotransferase is an indicator for better response to antiviral therapy in chronic hepatitis B

BackgroundEvidence shows people living with CHB even with a normal ALT (40U/L as threshold) suffer histological disease and there is still little research to evaluate the potential benefit of antiviral benefits in them.MethodsWe retrospectively examined 1352 patients who underwent liver biopsy from 2017 to 2021 and then obtained their 1-year follow-up data to analyze.ResultsALT levels were categorized into high and low, with thresholds set at &gt;29 for males and &gt;15 for females through Youden’s Index. The high normal ALT group showed significant histological disease at baseline (56.43% vs 43.82%, p&lt; 0.001), and better HBV DNA clearance from treatment using PSM (p=0.005). Similar results were obtained using 2016 AASLD high normals (male &gt;30, female &gt;19). Further multivariate logistic analysis showed that high normal ALT (both criterias) was an independent predictor of treatment (OR 1.993, 95% CI 1.115-3.560, p=0.020; OR 2.000, 95% CI 1.055-3.793, p=0.034) Both of the models had higher AUC compared with current scoring system, and there was no obvious difference between the two models (AUC:0.8840 vs 0.8835)ConclusionMale &gt;30 or female &gt;19 and Male &gt;29 or female&gt;15 are suggested to be better thresholds for normal ALT. Having a high normal ALT in CHB provides a potential benefit in antiviral therapy

Striatal dopamine depletion after MPTP treatment.

<p>*: <i>P</i><0.05,</p><p>***: <i>P</i><0.001 compared to CON;</p><p>##: <i>P</i><0.01,</p><p>###: <i>P</i><0.001 compared to SYN.</p><p>One-way ANOVA Newman-Keuls <i>post-hoc</i> test.</p><p>Striatal dopamine depletion after MPTP treatment.</p

Loss of striatal protein TH and increased dopamine turnover after MPTP treatment.

<p>Protein blots for striatal TH were analyzed TH/β-actin ratio and normalized by the results of CON (A, B). Dopamine turnover, which was analyzed by DOPAC/DA and HVA/DA ratio, exhibited significant increase after MPTP treatment (C). Data are presented as mean±SEM of 3 mice; *, compared to CON; #, compared to SYN; +, compared to MPTP. *, +, #: <i>P</i><0.05; **, ++, ##: <i>P</i><0.01; ***, ###, +++: <i>P</i><0.001 (one-way ANOVA Newman-Keuls <i>post-hoc</i> test).</p

Immunohistological analysis of DA neurons in the SNpc and TH positive neurites in the striatum.

<p>Representative micrographs of nigral sections immunostained for TH in mice at 4, 8 and 12 weeks after delivery of rAAV-GFP (CON: A, C and E) and rAAV-α-syn (SYN: B, D and F) vectors. Scale bar: 400μm. Illustration of striatal TH positive fiber density over time (H, J, L: rAAV-GFP; I, K, M: rAAV-α-syn). Scale bar: 50μm. Quantification of TH positive neurons in the SNpc and striatal TH immunoreactive fiber density was shown (G, N). Data are means ± SEM of 6 mice, **<i>P</i><0.01, ***<i>P</i><0.001 as compared to rAAV-GFP control (2-way ANOVA, Bonferroni <i>post hoc</i> test).</p

α-syn aggregation and nuclear distribution in nigral neurons after MPTP treatment.

<p>Double Immunofluorescence staining for NeuN (green) and <b>α</b>-syn (red) was performed to assess the condition of <b>α</b>-syn (antibody against <b>α</b>-syn, Santa Cruz, sc-7011-R). Small arrows denote dot-like accumulation of <b>α</b>-syn surround the nucleus after rAAV- <b>α</b>-syn transduction (E). More <b>α</b>-syn accumulation in cytoplasm (small arrows, K) and nucleus distribution (big arrow, K) in neurons of the <b>α</b>-syn and MPTP combined treatments. A-C: CON (rAAV-GFP+saline); D-F: SYN (rAAV- <b>α</b>-syn+saline); G-I: MPTP (rAAV-GFP+MPTP); J-L: SYN-MPTP (rAAV- <b>α</b>-syn+MPTP). Scale bar: 50um (A, B, D, E, G, H, J, K); 20μm (C, F, I, L).</p