Antiviral treatment alters the frequency of activating and inhibitory receptor-expressing natural killer cells in chronic Hepatitis B virus infected patients

Natural killer (NK) cells play a critical role in innate antiviral immunity, but little is known about the impact of antiviral therapy on the frequency of NK cell subsets. To this aim, we performed this longitudinal study to examine the dynamic changes of the frequency of different subsets of NK cells in CHB patients after initiation of tenofovir or adefovir therapy. We found that NK cell numbers and subset distribution differ between CHB patients and normal subjects; furthermore, the association was found between ALT level and CD158b+ NK cell in HBV patients. In tenofovir group, the frequency of NK cells increased during the treatment accompanied by downregulated expression of NKG2A and KIR2DL3. In adefovir group, NK cell numbers did not differ during the treatment, but also accompanied by downregulated expression of NKG2A and KIR2DL3. Our results demonstrate that treatment with tenofovir leads to viral load reduction, and correlated with NK cell frequencies in peripheral blood of chronic hepatitis B virus infection. In addition, treatments with both tenofovir and adefovir in chronic HBV infected patients induce a decrease of the frequency of inhibitory receptor+ NK cells, which may account for the partial restoration of the function of NK cells in peripheral blood following treatment

Superconductivity across Lifshitz transition and anomalous insulating state in surface K-dosed (Li0.8Fe0.2OH)FeSe

In the iron-based superconductors, understanding the relation between superconductivity and electronic structure upon doping is crucial for exploring the pairing mechanism. Recently it was found that in iron selenide (FeSe), enhanced superconductivity (Tc over 40K) can be achieved via electron doping, with the Fermi surface only comprising M-centered electron pockets. Here by utilizing surface potassium dosing, scanning tunneling microscopy/spectroscopy (STM/STS) and angle-resolved photoemission spectroscopy (ARPES), we studied the electronic structure and superconductivity of (Li0.8Fe0.2OH)FeSe in the deep electron-doped regime. We find that a {\Gamma}-centered electron band, which originally lies above the Fermi level (EF), can be continuously tuned to cross EF and contribute a new electron pocket at {\Gamma}. When this Lifshitz transition occurs, the superconductivity in the M-centered electron pocket is slightly suppressed; while a possible superconducting gap with small size (up to ~5 meV) and a dome-like doping dependence is observed on the new {\Gamma} electron pocket. Upon further K dosing, the system eventually evolves into an insulating state. Our findings provide new clues to understand superconductivity versus Fermi surface topology and the correlation effect in FeSe-based superconductors.Comment: 21 pages, 13 figure

Increased RPA1 gene dosage affects genomic stability potentially contributing to 17p13.3 duplication syndrome

A novel microduplication syndrome involving various-sized contiguous duplications in 17p13.3 has recently been described, suggesting that increased copy number of genes in 17p13.3, particularly PAFAH1B1, is associated with clinical features including facial dysmorphism, developmental delay, and autism spectrum disorder. We have previously shown that patient-derived cell lines from individuals with haploinsufficiency of RPA1, a gene within 17p13.3, exhibit an impaired ATR-dependent DNA damage response (DDR). Here, we show that cell lines from patients with duplications specifically incorporating RPA1 exhibit a different although characteristic spectrum of DDR defects including abnormal S phase distribution, attenuated DNA double strand break (DSB)-induced RAD51 chromatin retention, elevated genomic instability, and increased sensitivity to DNA damaging agents. Using controlled conditional over-expression of RPA1 in a human model cell system, we also see attenuated DSB-induced RAD51 chromatin retention. Furthermore, we find that transient over-expression of RPA1 can impact on homologous recombination (HR) pathways following DSB formation, favouring engagement in aberrant forms of recombination and repair. Our data identifies unanticipated defects in the DDR associated with duplications in 17p13.3 in humans involving modest RPA1 over-expression

Radiation fog properties in two consecutive events under polluted and clean conditions in the Yangtze River Delta, China: a simulation study

Aerosol–cloud interaction (ACI) in fog and planetary boundary layer (PBL) conditions plays critical roles in the fog life cycle. However, it is not clear how ACI in the first fog (Fog1) affects the PBL and subsequently affects ACI in the second fog (Fog2), which is important information for understanding the interaction between ACI and the PBL, as well as their effects on fog properties. To fill this knowledge gap, we simulate two successive radiation fog events in the Yangtze River Delta, China, using the Weather Research and Forecasting model coupled with Chemistry (WRF-Chem). Our simulations indicate that the PBL conditions conducive to Fog2 formation are affected by ACI with high aerosol loading in Fog1; subsequently, the PBL promotes ACI in Fog2, resulting in a higher liquid water content, higher droplet number concentration, smaller droplet size, larger fog optical depth, wider fog distribution, and longer fog lifetime in Fog2 than in Fog1. This phenomenon is related to the following physical factors. The first factor involves meteorological conditions conducive to Fog2 formation, including low temperature, high humidity, and high stability. The second factor is the feedbacks between microphysics and radiative cooling. A higher fog droplet number concentration increases the liquid water path and fog optical depth, thereby enhancing long-wave radiative cooling and condensation near the fog top. The third factor is the feedbacks between macrophysics, radiation, and turbulence. A higher fog top presents stronger long-wave radiative cooling near the fog top than near the fog base, which weakens temperature inversion and strengthens turbulence, ultimately increasing the fog-top height and fog area. In summary, under polluted conditions, ACI postpones the dissipation of Fog1 owing to these two feedbacks and generates PBL meteorological conditions that are more conducive to the formation of Fog2 than those prior to Fog1. These conditions promote the earlier formation of Fog2, further enhancing the two feedbacks and strengthening the ACI in Fog2. Our findings are critical for studying the interaction between aerosols, fog, and the PBL; moreover, they shed new light on ACI.</p

Biodistribution and in Vivo Activities of Tumor-Associated Macrophage-Targeting Nanoparticles Incorporated with Doxorubicin

Tumor-associated macrophages (TAMs) are increasingly considered a viable target for tumor imaging and therapy. Previously, we reported that innovative surface-functionalization of nanoparticles may help target them to TAMs. In this report, using poly(lactic-co-glycolic) acid (PLGA) nanoparticles incorporated with doxorubicin (DOX) (DOX-NPs), we studied the effect of surface-modification of the nanoparticles with mannose and/or acid-sensitive sheddable polyethylene glycol (PEG) on the biodistribution of DOX and the uptake of DOX by TAMs in tumor-bearing mice. We demonstrated that surface-modification of the DOX-NPs with both mannose and acid-sensitive sheddable PEG significantly increased the accumulation of DOX in tumors, enhanced the uptake of the DOX by TAMs, but decreased the distribution of DOX in mononuclear phagocyte system (MPS), such as liver. We also confirmed that the acid-sensitive sheddable PEGylated, mannose-modified DOX-nanoparticles (DOX-AS-M-NPs) targeted TAMs because depletion of TAMs in tumor-bearing mice significantly decreased the accumulation of DOX in tumor tissues. Furthermore, in a B16-F10 tumor-bearing mouse model, we showed that the DOX-AS-M-NPs were significantly more effective than free DOX in controlling tumor growth but had only minimum effect on the macrophage population in mouse liver and spleen. The AS-M-NPs are promising in targeting cytotoxic or macrophage-modulating agents into tumors to improve tumor therapy

Auction market placement and a rest stop during transportation affect the respiratory bacterial microbiota of beef cattle

BackgroundBovine respiratory disease (BRD) is a significant health problem in beef cattle production, resulting in considerable economic losses due to mortalities, cost of treatment, and reduced feed efficiency. The onset of BRD is multifactorial, with numerous stressors being implicated, including transportation from farms to feedlots. In relation to animal welfare, regulations or practices may require mandatory rest times during transportation. Despite this, there is limited information on how transportation and rest stops affect the respiratory microbiota.ResultsThis study evaluated the effect of cattle source (ranch-direct or auction market-derived) and rest stop duration (0 or 8 h of rest) on the upper respiratory tract microbiota and its relationship to stress response indicators (blood cortisol and haptoglobin) of recently weaned cattle transported for 36 h. The community structure of bacteria was altered by feedlot placement. When cattle were off-loaded for a rest, several key bacterial genera associated with BRD (Mannheimia, Histophilus, Pasteurella) were increased for most sampling times after feedlot placement for the ranch-direct cattle group, compared to animals given no rest stop. Similarly, more sampling time points had elevated levels of BRD-associated genera when auction market cattle were compared to ranch-direct. When evaluated across time and treatments several genera including Mannheimia, Moraxella, Streptococcus and Corynebacterium were positively correlated with blood cortisol concentrations.ConclusionThis is the first study to assess the effect of rest during transportation and cattle source on the respiratory microbiota in weaned beef calves. The results suggest that rest stops and auction market placement may be risk factors for BRD, based solely on increased abundance of BRD-associated genera in the upper respiratory tract. However, it was not possible to link these microbiota to disease outcome, due to low incidence of BRD in the study populations. Larger scale studies are needed to further define how transportation variables impact cattle health