The role of sex hormones and receptors in HBV infection and development of HBV-related HCC.

Gender disparity in hepatitis B virus (HBV)-related diseases has been extensively documented. Epidemiological studies consistently reported that males have a higher prevalence of HBV infection and incidence of hepatocellular carcinoma (HCC). Further investigations have revealed that sex hormone-related signal transductions play a significant role in gender disparity. Sex hormone axes showed significantly different responses to virus entry and replication. The sex hormones axes change the HBV-specific immune responses and antitumor immunity. Additionally, Sex hormone axes showed different effects on the development of HBV-related disease. But the role of sex hormones remains controversial, and researchers have not reached a consensus on the role of sex hormones and the use of hormone therapies in HCC treatment. In this review, we aim to summarize the experimental findings on sex hormones and provide a comprehensive understanding of their roles in the development of HCC and their implications for hormone-related HCC treatment.

Posttranslational modifications of ACE2 protein: Implications for SARS-CoV-2 infection and beyond.

The present worldwide pandemic of coronavirus disease 2019 (COVID-19) has highlighted the important function of angiotensin-converting enzyme 2 (ACE2) as a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry. A deeper understanding of ACE2 could offer insights into the mechanisms of SARS-CoV-2 infection. While ACE2 is subject to regulation by various factors in vivo, current research in this area is insufficient to fully elucidate the corresponding pathways of control. Posttranslational modification (PTM) is a powerful tool for broadening the variety of proteins. The PTM study of ACE2 will help us to make up for the deficiency in the regulation of protein synthesis and translation. However, research on PTM-related aspects of ACE2 remains limited, mostly focused on glycosylation. Accordingly, a comprehensive review of ACE2 PTMs could help us better understand the infection process and provide a basis for the treatment of COVID-19 and beyond.

Optical Waveguiding Organic Single Crystals Exhibiting Physical and Chemical Bending Features.

Bendable (elastic and plastic) organic single crystals have been widely studied as emerging flexible materials with highly ordered packing structures. However, even though manifold bendable organic crystals have been recently reported, most of them bend in response to only one stimulus. Herein, we report an organic single crystal of (Z)-4-(1-cyano-2-(4-(dimethylamino)phenyl)vinyl)benzonitrile, which bends under external stress (physical process) and also hydrochloric acid atmosphere (chemical process). This observation indicates that a single organic crystal, whose structure has been optimized simultaneously at both the molecular and supramolecular levels, may display multiple crystal-bending modes. Furthermore, the crystals exhibit bright orange-yellow emission and can serve as an active low-loss optical waveguide in both the straight and the bent state, which indicates a potential optical application.

A Flexible Organic Single Crystal with Plastic-Twisting and Elastic-Bending Capabilities and Polarization-Rotation Function.

Flexible organic single crystals capable of plastic or elastic deformations have a variety of potential applications. Although the integration of plasticity and elasticity in a crystal is theoretically possible and it may cause rich and complex deformations which are highly demanded for potential applications, the integration is hard to realize in practice. Here, we show that through utilizing different modes of external forces for influencing molecular packing in different crystallographic directions, plastic helical twisting and elastic bending can both be achieved for a crystal, and they can even be realized simultaneously. Detailed crystallographic analyses and contrast experiments disclose the mechanisms behind these two kinds of distinct deformations and their mutual compatibility. Based on the plastically twistable nature of the crystal, a new application field of flexible organic single crystals, namely polarization rotators, is successfully opened up.

Self-Waveguide Single-Benzene Organic Crystal with Ultralow-Temperature Elasticity as a Potential Flexible Material.

With the increasing popularity and burgeoning progress of space technology, the development of ultralow-temperature flexible functional materials is a great challenge. Herein, we report a highly emissive organic crystal combining ultralow-temperature elasticity and self-waveguide properties (when a crystal is excited, it emits light from itself, which travels through the crystal to the other end) based on a simple single-benzene emitter. This crystal displayed excellent elastic bending ability in liquid nitrogen (LN). Preliminary experiments on optical waveguiding in the bent crystal demonstrated that the light generated by the crystal itself could be confined and propagated within the crystal body between 170 and -196 °C. These results not only suggest a guideline for designing functional organic crystals with ultralow-temperature elasticity but also expand the application region of flexible materials to extreme environments, such as space technology.

Highly Elastic Organic Crystals for Flexible Optical Waveguides.

The study of elastic organic single crystals (EOSCs) has emerged as a cutting-edge research of crystal engineering. Although a few EOSCs have been reported recently, those suitable for optical/optoelectronic applications have not been realized. Here, we report an elastic crystal of a Schiff base, (E)-1-(4-(dimethylamino)phenyl)iminomethyl-2-hydroxyl-naphthalene. The crystal is highly bendable under external stress and able to regain immediately its original straight shape when the stress is released. It displays bright orange-red emission with a high fluorescence quantum yield of 0.43. Intriguingly, it can serve as a low-loss optical waveguide even at the highly bent state. Our result highlights the feature and utility of "elasticity" of organic crystals.

Suitability of Embedded Liquid Cooling and Heat Generation for Chips.

Embedded liquid cooling is a preferred solution for dissipating the heat generated by high-power chips. The cooling capacity and pump power consumption of embedded liquid cooling heat sinks differ significantly between different structures. To achieve an accurate match between cooling capacity and heat dissipation requirements, the selection of a liquid-cooled heat sink should be carefully considered in conjunction with the heat dissipation needs of heat sources in real-world thermal management issues. Based on the manufacturing limitations on chip temperature and microchannel pressure, a composite performance index function was developed to assess the cooling capacity and cooling cost of the heat sink. This allowed for the establishment of an evaluation standard to determine the suitability of embedded liquid cooling and heat sink for the heat source. In this study, the suitability of four microchannel heat sinks with the same feature length and fin volume was evaluated under various thermal load conditions. The results show that the best-suited heat sink changes with variations in the thermal load of the chip. In the example, when the heat source was homogeneous at 100 W, the circular section pin fins have an optimal suitability of 0.928 for Re = 500. When the heat source was a heterogeneous heat source with a power of 100 W, the value of Θ was found to be 0.389. Additionally, the optimal suitability of drop section pin fins for Re = 971.5 was determined to be 0.862.

CDK4/6 inhibitor palbociclib promotes SARS-CoV-2 cell entry by down-regulating SKP2 dependent ACE2 degradation.

Coronavirus disease 2019 (COVID-19) outbreak has become a global pandemic. CDK4/6 inhibitor palbociclib was reported to be one of the top-scored repurposed drugs to treat COVID-19. As the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry, expression level of angiotensin-converting enzyme 2 (ACE2) is closely related to SARS-CoV-2 infection. In this study, we demonstrated that palbociclib and other methods could arrest cells in G0/G1 phase and up-regulate ACE2 mRNA and protein levels without altering its subcellular localization. Palbociclib inhibited ubiquitin-proteasome and lysosomal degradation of ACE2 through down-regulating S-phase kinase-associated protein 2 (SKP2). In addition, increased ACE2 expression induced by palbociclib and other cell cycle arresting compounds facilitated pseudotyped SARS-CoV-2 infection. This study suggested that ACE2 expression was down-regulated in proliferating cells. Cell cycle arresting compounds could increase ACE2 expression and facilitate SARS-CoV-2 cell entry, which may not be suitable therapeutic agents for the treatment of SARS-CoV-2 infection.

Research on Intelligent Distribution of Liquid Flow Rate in Embedded Channels for Cooling 3D Multi-Core Chips.

A numerical simulation model of embedded liquid microchannels for cooling 3D multi-core chips is established. For the thermal management problem when the operating power of a chip changes dynamically, an intelligent method combining BP neural network and genetic algorithm is used for distribution optimization of coolant flow under the condition with a fixed total mass flow rate. Firstly, a sample point dataset containing temperature field information is obtained by numerical calculation of convective heat transfer, and the constructed BP neural network is trained using these data. The "working condition-flow distribution-temperature" mapping relationship is predicted by the BP neural network. The genetic algorithm is further used to optimize the optimal flow distribution strategy to adapt to the dynamic change of power. Compared with the commonly used uniform flow distribution method, the intelligently optimized nonuniform flow distribution method can further reduce the temperature of the chip and improve the temperature uniformity of the chip.

Thermal-Hydrodynamic Behavior and Design of a Microchannel Pin-Fin Hybrid Heat Sink.

A three-dimensional convective heat transfer model of a microchannel pin-fin hybrid heat sink was established. Considering the non-uniform heat generation of 3D stacked chips, the splitting distance of pin-fins was optimized by minimizing the maximum heat sink temperature under different heat fluxes in the hotspot, the Reynolds numbers at the entrance of the microchannel, and the proportions of the pin-fin volume. The average pressure drop and the performance evaluation criteria were considered to be the performance indexes to analyze the influence of each parameter on the flow performance and comprehensive performance, respectively. The results showed that the maximum temperature of the hybrid heat sink attained a minimum value with an increase in the splitting distance. The average pressure drop in the center passage of the microchannel first increased and then decreased. Furthermore, the optimal value could not be simultaneously obtained with the maximum temperature. Therefore, it should be comprehensively considered in the optimization design. The heat flux in the hotspot was positively correlated with the maximum heat sink temperature. However, it had no effect on the flow pressure drop. When the Reynolds number and the pin-fin diameter increased, the maximum heat sink temperature decreased and the average pressure drop of the microchannel increased. The comprehensive performance of the hybrid heat sink was not good at small Reynolds numbers, but it significantly improved as the Reynolds number gradually increased. Choosing a bigger pin-fin diameter and the corresponding optimal value of the splitting distance in a given Reynolds number would further improve the comprehensive performance of a hybrid heat sink.

Naturally occurring pre-S mutations promote occult HBV infection by affecting pre-S2/S promoter activity.

Occult hepatitis B virus (HBV) infection (OBI) has non-negligible clinical significance, but the mechanism of its occurrence remains unclear. Growing evidence suggests that mutations in the pre-S region of HBV genome may be associated with the occurrence of OBI. However, the role of pre-S mutations in OBI and its molecular mechanism was not fully understand. Here, the pre-S sequences from 307 OBI blood donors and 293 hepatitis B surface protein (HBsAg)-positive blood donors were obtained, and we observed a higher frequency of naturally occurring pre-S mutations in OBI donors infected with genotype B/C HBV than in HBsAg-positive donors, suggesting their potential positive role in OBI. In both genotype B and C, several pre-S mutants resulted in markedly reduced HBsAg production in vitro. In particular, the T68I, S78N and N98T mutants of genotype B were proven to significantly decrease the HBsAg synthesis by affecting the pre-S2/S promoter activity, and thereby promoting the occurrence of OBI.

Circulating immune complexes and mutations of HBsAg are associated with the undetectable HBsAg in anti-HBs and HBeAg positive occult hepatitis B virus infection.

Introduction: Occult hepatitis B virus infection (OBI) is an HBsAg negative state in HBV infection with usually inactive HBV replication. However, there were a minority of individuals with positive HBeAg and anti-HBs among OBI blood donors and few studies have focused on this unusual serological pattern. Methods: 2022 plasma of blood donors that preliminary screened reactive for HBV DNA and non-reactive for HBsAg were collected from 16 provinces in China from 2015 to 2018. HBV DNA and HBsAg in these samples were retested using the Cobas TaqScreen MPX test and ARCHITECT HBsAg Quantitative II assay. Lumipulse HBsAg-HQ assay and polyethylene glycol (PEG)-double precipitation following HCl and trypsin digestion were performed to detect HBsAg from HBsAg-anti-HBs circulating immune complexes (CICs). Results: 1487 of 2022 samples were positive for Cobas HBV DNA test and non-reactive for ARCHITECT HBsAg assay, while 404 of them were positive using Lumipulse HBsAg-HQ assay. 10 HBsAg-/anti-HBs+/HBeAg+ OBI blood donor samples were further dissociated and HBsAg-CICs were detected in 7 samples. Sequencing analysis showed that D44N, N98T, G73S, Del 56-116, and I161T occurred in the pre-S region, and immune escape mutations such as P127T, F134L, G145R, V168A, and I126T/S in the S region were found. Discussion: In conclusion, there were a minority of HBsAg-/anti-HBs+/HBeAg+ individuals in OBI blood donors. The undetectable HBsAg in these individuals was mainly due to HBsAg-CICs. Immune escape-associated mutations also happened under the host's selective pressure. HBsAg dissociation methods or Lumipulse HBsAg-HQ assay is recommended to distinguish these individuals.

Low seroprevalence of hepatitis delta virus co-infection in hepatitis B virus-infected blood donors in China: A multicenter study.

Hepatitis delta virus (HDV) coinfected with HBV causes severe viral hepatitis, however, the number of HDV infection may be underestimated. In the present study, we enrolled 1,141,331 blood donations, routinely tested for HBsAg and/or HBV DNA, from 21 blood establishments in China. 2,690 donors were HBsAg and/or HBV DNA positive after screening tests. After verification of HBsAg and HBV DNA, 1,490 samples were HBsAg confirmed-positive, including 1,459 HBV DNA-positive samples, and 825 samples were seronegative but HBV DNA positive. We first analyzed demographic characteristics of involved 2,690 donors with different HBV infection status and found the proportions of males, the older donors, workers and farmers were higher in HBsAg-/HBV DNA+ group. Then we evaluated specificity of HDV IgG and IgM antibody assays with 375 HBsAg and HBV DNA confirmed-negative samples, and 374 were tested negative using the two assays, respectively, suggesting a specificity of 99.73% for both assays (374/375, 95% Cl: 98.51-99.95%). Subsequently, we tested for HDV IgG and IgM of 2,315 HBsAg and/or HBV DNA confirmed-positive samples, and nine showed reactivity for IgG, while two were reactive for IgM. All these 11 reactive samples were tested again with another HDV pan-Ig and IgM testing assays and HDV RNA, and only one donor was identified as HDV IgG positive and HDV RNA negative, showing an HDV seroprevalence of 0.067% (95%CI: 0.012-0.38%) among HBsAg-positive blood donors in China. The positive donor was followed up for 2 years after the donation date, and decreased antibody titer of HDV IgG and HBsAg conversion were observed, and the infection status of the donor was HDV infection with recovery and occult hepatitis B virus infection with genotype C2. These results indicated a low seroprevalence of HDV infection among blood donors and a low risk of HDV transmission through blood transfusion in China.

Engineering Mechanical Compliance of an Organic Compound toward Flexible Crystal Lasing Media.

Recently, organic crystals with mechanical flexibility have been emerging as a hot research topic due to their great potentials in flexible optoelectronics. However, organic crystals exhibiting elastic bending or plastic bending are relatively rare. In this study, we proposed a strategy to improve the probability of crystal flexibility as well as to regulate the mechanical properties by controlling polymorphism. Three different emissive organic polymorphs Cry-G, Cry-Y, and Cry-O with elastic, plastic, and brittle natures, respectively, were obtained by fine-tuning crystallization conditions of a diaryl ß-diketone compound. Cry-G was found to transduce light and amplify the self-waveguided emission efficiently along the crystal body in the elastically bent state, demonstrating its multifunctional applications in flexible optical devices. This study is of great scientific significance not only to engineer mechanical compliance of organic crystals but also to highlight the utility of "crystal flexibility".

Polymorph-Dependent Luminescence Response to Acid Vapors and Its Application in Safety Protection of File Information.

A Schiff base, (E)-1-(phenylimino)methyl-2-hydroxylnaphthalene (PIHN), was found to form both nonluminescent and luminescent polymorphs. A unique luminescence "turn on" behavior was observed when the nonluminescent polymorph was fumed with the vapor of aliphatic acids with two or three carbons in the main chain, while the luminescent polymorphs almost did not change the emission color under the same condition. As we know, this is the first report on polymorph-dependent acid response which discloses the influence of crystalline phase on acid-responsive behavior. The formation of hydrogen bonds between PIHN and aliphatic acid is proposed to be the reason for the responsive behavior of the nonemissive polymorph, and such a mechanism is different from the common protonation mechanism. A novel safety protection method of file information has been developed based on the polymorph-dependent luminescence response of PIHN. In addition, we disclose that a crystalline form could show multiple responsive behaviors toward different acids, which benefits the further design of novel acid sensors, such as the sensors that can qualitatively analyze the species of the acid source in an acidic environment.