The complete genome sequence of a putative novel cytorhabdovirus identified in Chelidonium majus in China.

A new cytorhabdovirus, tentatively named "chelidonium yellow mottle associated virus" (CheYMaV), was identified in Chelidonium majus with yellow mottle symptoms by high-throughput sequencing and RT-PCR. Its genome is 12,121 nucleotides in length and contains eight open reading frames (ORFs) in the order 3'-N-P'-P-P3-M-G-P6-L-5'. Amino acid sequence comparisons between the putative proteins of CheYMaV and the corresponding proteins of other cytorhabdoviruses showed that it shares the highest sequence similarity with Trifolium pratense virus A (TpVA, MH982250) and Glehnia littoralis virus 1 (GllV1, BK014304), but with sequence identity values below the species demarcation threshold for cytorhabdoviruses (< 80%). Phylogenetic analysis showed that CheYMaV is most closely related to TpVA and GllV1. CheYMaV should therefore be considered a new member of the genus Cytorhabdovirus. This is the first report of a cytorhabdovirus identified in Chelidonium majus.

Molecular identification of a putative novel varicosavirus in Agastache rugosa in China.

A putative novel virus was identified in Agastache rugosa in China and tentatively named "Agastache rugosa-associated varicosavirus" (ARaVV). The nearly complete genome sequence of ARaVV was obtained through RNA sequencing (RNA-seq) and subsequent RT-PCR. The ARaVV genome consists of two negative-sense single-stranded RNA segments that are 6428 and 3862 nucleotides (nt) in size, respectively. RNA1 encodes a large polymerase (L), and RNA2 encodes a putative nucleocapsid protein (N), protein 2 (P2), and protein 3 (P3). The L protein shared the highest amino acid (aa) sequence identity (51.3%) with Erysimum virus 1 (EryV1, BK061766.1). The N, P2, and P3 shared the highest aa sequence identity (33.1%, 14.0%, and 24.2%) with Leucanthemum virus 1, Raphanus virus 1, and Spinach virus 1, respectively. Phylogenetic analysis based on amino acid sequences of the L protein showed that ARaVV clustered in a clade with the varicosaviruses, indicating that ARaVV is a putative new member of the genus Varicosavirus.

First report of cucumber green mottle mosaic virus infecting Cynanchum rostellatum in China.

Cucumber green mottle mosaic virus (CGMMV) was first discovered on cucumber in the United Kingdom in 1935 (Ainsworth, 1935), and has spread worldwide except to Antarctica (Jones, 2021). Given its extensive damage, it is considered an important pathogen on global cucurbit plants and fruit crops. In China, CGMMV was first reported on pumpkin in Guangxi Province in 2003 (Qin et al., 2005), and occurred on 34 plants species across 23 provinces (Liu et al., 2016). Cynanchum rostellatum is a member of the family Apocynaceae. In July 2021, leaves of C. rostellatum exhibiting virus-like symptoms (yellowing, severe crinkling, deformation) were observed and collected in Liaoning Province, China. Aphids were also observed on the leaves and stems (Fig. S1) of the plants and were collected. Total RNA was extracted from diseased leaves following the CTAB method, followed by the depletion of ribosomal RNAs (rRNA) with TIANSeq rRNA Depletion Kit (Tiangen, China). The RNAs were, then processed into a DNBSEQ LncRNA-Seq library, and sequenced on the MGISEQ-2000 platform at BGI Genomics (Wuhan, China). A total of 106.98 M clean reads were obtained after data filtering using SOAPnuke software (BGI, China). The clean reads were assembled into contigs using CLC Genomics Workbench 11 (Qiagen, USA) and Trinity v2.0.6 (Haas et al., 2013). A contig (4,760 reads, average coverage:73.76) of 6,391 nucleotides was found to share the highest sequence identity (99.83%) with CGMMV isolate GDLZ (MK933286), irrespective of other virus-like contigs related to Polerovirus and Totivirus. Based on the genome of GDLZ isolate, seven specific primers (Table S1) were designed to amplify the full viral genomic sequences using a PrimeScriptTM One-Step RT-PCR Kit. Seven expected amplicons were obtained, cloned, and sequenced. The complete genome was determined to be 6,423 nucleotides (GenBank accession number OR854819) in length and designated as LNMJ isolate. LNMJ shared 96.8%-99.7% nucleotide sequence identities with CGMMV isolates from China. Phylogenetic analysis based on the complete genome sequences showed that LNMJ clustered together with CGMMV isolates hn (GenBank accession number KC851866), GDLZ (GenBank accession number MK933286), and JD8 (GenBank accession number KM873784) from China. The specific primers LM-TJ-3F/3R were designed to determine the virus-symptom association for LNMJ, and all twelve symptomatic C. rostellatum plants collected from fields tested positive for LNMJ. Two out of six randomly selected aphids from the diseased plants also tested positive. To further prove its infectivity, LNMJ was inoculated mechanically onto ten healthy Nicotiana benthamiana plants, and the results indicated a high infection rate of 80% (8/10), at 30 days post-inoculation despite no distinct symptoms observed. To our knowledge, this is the first report of the natural infection of C. rostellatum plants with CGMMV. C. rostellatum is a widespread herb in China (Wei et al., 2019) and more surveys are needed to determine the distribution of CGMMV. The habitats of C. rostellatum span diverse agroecological zones, and thus our study underscores the potential spillover of CGMMV to neighboring crops as a significant risk.

Inhibition of annexin A7 suppresses senescence-associated heterochromatin foci formation and senescence through the AMPK/mTOR pathway in human dermal fibroblasts.

Senescence-associated heterochromatin foci (SAHF) is often used as a biological marker for senescent cells, but the regulation of its formation process is unclear. To find a new modulator of SAHF, we screened our chemical small molecules and found 7-amino-2,3,4,5-tetrahedrobenzo[b][1,4] oxazepin-3-ol (ABO) that was identified as an inhibitor of annexin A7 GTPase (ANXA7) dramatically suppressed the aggregation of heterochromatin protein (HP1γ), an indicator of SAHF. To understand its action mechanism, we first observed the changes in the karyoplasmic ratio of ANXA7 because HP1γ mainly located in the nucleus. The results showed that ABO elevated the protein level of ANXA7 in the nucleus. Therefore, we raised a hypothesis that ANXA7 interacted with HP1γ and regulated its phosphorylation, which is closely related to the formation of SAHF. The co-immunoprecipitation and Western blot experiment results showed that ANXA7 had no direct interaction with HP1γ, however, the phosphorylation of HP1γ was increased by ABO, which suggested that ANXA7 indirectly regulated HP1γ phosphorylation. Then, based on our previous discovery of ANXA7 interacting with AMP-activated protein kinase (AMPK), we investigated the effect of the AMPK/mammalian target of rapamycin (mTOR) signaling pathway on ABO-increased phosphorylation of HP1γ. We found that ABO decreased AMPK phosphorylation and increased the phosphorylation level and activity of mTOR. In the presence of an AMPK activator or mTOR inhibitor, ABO could not increase HP1γ phosphorylation. As a result, ABO inhibited the senescence of human dermal fibroblasts (HDFs). In this study, we found that ANXA7 was a new regulator of SAHF, it could regulate the formation of SAHF through the AMPK/mTOR pathway. The data suggested that ABO could be used as a powerful tool to inhibit the replicative senescence of HDFs.

Esterase D interacts with metallothionein 2A and inhibits the migration of A549 lung cancer cells in vitro.

Esterase D (ESD) is a nonspecific esterase widely distributed in various organisms. ESD plays an important role in regulating cholesterol efflux, inhibiting viral replication and lung cancer growth. MT2A (metallothionein 2A) is the most important isoform of metallothionein (MTs) in human and high expression of MT2A in tumors represents poor prognosis and metastatic behavior. However, there are no reports about the molecular mechanism of ESD in the regulation of tumor metastasis. In this study, we found for the first time that activation ESD promoted its interaction with MT2A and decreased the protein level of MT2A, which resulting in the concentration of free zinc ions up-regulated, and inhibited the migration of A549 lung cancer cells in vitro.

Ultrastable Super-Tonks-Girardeau Gases under Weak Dipolar Interactions.

The highly excited super-Tonks-Girardeau (sTG) gas was recently observed to be extremely stable in the presence of a weak dipolar repulsion. Here we reveal the underlying reason for this mysterious phenomenon. By exactly solving the trapped small clusters with both contact and dipolar interactions, we show that the reason lies in the distinct spectral responses between sTG gas and its decaying channel (bound state) when a weak dipolar interaction is present. Specifically, a tiny dipolar force can produce a visible energy shift for the localized bound state, but can hardly affect the extended sTG branch. As a result, the avoided level crossing between two branches is greatly modified in both location and width in the parameter axis of coupling strength, leading to a more (less) stable sTG gas for a repulsive (attractive) dipolar force. These results, consistent with experimental observations, are found to robustly apply to both bosonic and fermionic systems.

Quartet Superfluid in Two-Dimensional Mass-Imbalanced Fermi Mixtures.

Quartet superfluid (QSF) is a distinct type of fermion superfluidity that exhibits high-order correlation beyond the conventional BCS pairing paradigm. In this Letter, we report the emergent QSF in 2D mass-imbalanced Fermi mixtures with two-body contact interactions. This is facilitated by the formation of a quartet bound state in vacuum that consists of a light atom and three heavy fermions. For an optimized heavy-light number ratio 3:1, we identify QSF as the ground state in a considerable parameter regime of mass imbalance and 2D coupling strength. Its unique high-order correlation can be manifested in the momentum-space crystallization of a pairing field and density distribution of heavy fermions. Our results can be readily detected in Fermi-Fermi mixtures nowadays realized in cold atoms laboratories, and meanwhile shed light on exotic superfluidity in a broad context of mass-imbalanced fermion mixtures.

ZBM-H-induced activation of GRP78 ATPase promotes apoptosis via annexin A7 in A549 lung cancer cells.

Hypochlorous acid (HOCl) is an essential signal for the regulation of cancer cell fate, including autophagy and apoptosis. HOCl regulated autophagy by affecting the oxidation modification of glucose-regulated protein 78 (GRP78) and the activity of GRP78 ATPase. The mechanism of GRP78 ATPase in cell apoptosis has however not yet been clarified. Here we reported that ZBM-H, as a probe of HOCl, was able to directly bind to GRP78 in the presence or absence of ATP. Following ZBM-H treatment, the interaction between GRP78 and annexin A7 (ANXA7) was promoted, and this was accompanied by increased phosphorylation of integrin ß4 (ITGB4). In addition, ZBM-H enhanced the phosphorylation of ANXA7. ABO, an inhibitor of ANXA7, inhibited ZBM-H-induced ITGB4 phosphorylation and apoptosis, while ANXA7 activator SEC had opposite effect. Collectively, these data provide new evidence for the mechanism by which ZBM-H-induced activation of GRP78 ATPase regulates apoptosis of A549 lung cancer cells.

Universal Tetramer and Pentamer Bound States in Two-Dimensional Fermionic Mixtures.

We study the emergence of universal tetramer and pentamer bound states in the two-dimensional (N+1) system, which consists of N identical heavy fermions interacting with a light atom. We show that the critical heavy-light mass ratio to support a (3+1) tetramer below the trimer threshold is 3.38, and to support a (4+1) pentamer below the tetramer threshold is 5.14. While the ground state tetramer and pentamer are both with zero total angular momentum, they exhibit very different density distributions and correlations in momentum space, due to their distinct angular momentum decompositions in the dimer-fermion frame. These universal bound states can be accessible by a number of Fermi-Fermi mixtures now realized in cold atoms laboratories, which also suggest novel few-body correlations dominant in their corresponding many-body systems.

A new activator of esterase D decreases blood cholesterol level through ESD/JAB1/ABCA1 pathway.

Excessively high cholesterol content in the blood leads to nonalcohol fatty liver disease (NAFLD) and arteriosclerosis. Although there are increasing publications and patent applications to lower blood cholesterol with small chemical molecules, limited effective drugs can be available in clinic. It is necessary to uncover new targets and drugs to alleviate high cholesterol. Esterase D (ESD) is abundant in liver and it remains unknown about its role in cholesterol metabolism. Here we reported that small chemical molecule fluorescigenic pyrazoline derivative 5 (FPD5), a new ESD activator, could effectively reverse high blood cholesterol level and prevent fatty liver and arteriosclerosis in apoE-/- mice fed the high-fat diet. We also observed that FPD5 could reduce oxidized low density lipoprotein (oxLDL)-induced formation of foam cells. To further investigate the mechanism of FPD5 action on blood cholesterol modulation, we found that ESD trigged by FPD5 was aggregated in lysosome and interacted with Jun activation domain binding protein 1 (JAB1). ESD served as a deacetylase to remove Thr89 acetylation of JAB1 and increased its activity; thus, promoting the ATP-binding cassette transporters A1 (ABCA1) to accelerate cholesterol efflux. Our findings demonstrate that FPD5 decreases blood cholesterol level to ameliorate NAFLD and arteriosclerosis through ESD/JAB1/ABCA1 pathway, and ESD functions as a novel nonclassical deacetylase that hydrolyzes serine/threonine acetyl group. Our findings not only highlight that FPD5 may be a pioneer drug for alleviating blood cholesterol but also indicate that ESD is a potential drug target that promotes cholesterol metabolism.

Borromean Droplet in Three-Component Ultracold Bose Gases.

We investigate droplet formation in three-component ultracold bosons. In particular, we identify the formation of a Borromean droplet, where only the ternary bosons can form a self-bound droplet while any binary subsystems cannot, as the first example of Borromean binding due to a collective many-body effect. Its formation is facilitated by an additional attractive force induced by the density fluctuation of a third component, which enlarges the mean-field collapse region in comparison to the binary case and renders the formation of a Borromean droplet after incorporating the repulsive force from quantum fluctuations. Outside the Borromean regime, we demonstrate an interesting phenomenon of droplet phase separation due to the competition between ternary and binary droplets. We further show that the transition between different droplets and gas phase can be conveniently tuned by boson numbers and interaction strengths. The study reveals the rich physics of a quantum droplet in three-component boson mixtures and sheds light on the more intriguing many-body bound state formed in multicomponent systems.

Promoting TTC4 and HSP70 interaction and translocation of annexin A7 to lysosome inhibits apoptosis in vascular endothelial cells.

We previously demonstrated that Tetraticopeptide 4 (TTC4) inhibited apoptosis in vascular endothelial cells (VEC) deprived of serum and fibroblast growth factor 2 (FGF-2). In this study, we aimed to resolve the mechanism of TTC4 inhibiting VEC apoptosis. TTC4, predicted as a HSP70 co-chaperone protein, may regulate the fate of cells by affecting the activity of HSP70, however, there is no experimental evidence showing the interaction of TTC4 and HSP70. Using Co-immunoprecipitation (Co-IP), we demonstrated that TTC4 interacted with HSP70. If HSP70 was knockdown, TTC4 no longer suppressed apoptosis. Furthermore, we found ABO, an inhibitor of annexin A7 (ANXA7) GTPase, could promote the interaction of TTC4 and HSP70 and the translocation of ANXA7 to lysosome. At the same time, ABO inhibited the interaction of HSP70 and ANXA7. Moreover, Akt, as a downstream effector of HSP70 was upregulated, and ANXA7 translocating to lysosome protected the stability of lysosomal membrane. Here, we discovered a special mechanism by which TTC4 inhibited apoptosis via HSP70 in VECs. On the one hand, increasing TTC4 and HSP70 interaction upregulated Akt that inhibited apoptosis. On the other hand, decreasing HSP70 and ANXA7 interaction promoted the translocation of ANXA7 to lysosome, which inhibited apoptosis through protecting the lysosomal membrane stability.

Esterase D stabilizes FKBP25 to suppress mTORC1.

BACKGROUND: Esterase D (ESD) is a nonspecific esterase that detoxifies formaldehyde. Many reports have stated that ESD activity is associated with a variety of physiological and pathological processes. However, the detailed signaling pathway of ESD remains poorly understood. METHODS: Considering the advantages of the small chemical molecule, our recent work demonstrated that 4-chloro-2-(5-phenyl-1-(pyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl) phenol (FPD5) activates ESD, and will be a good tool for studying ESD further. Firstly, we determined the interaction between ESD and FK506 binding protein 25 (FKBP25) by yeast two-hybrid assay and co-immunoprecipitation (CO-IP) and analyzed the phosphorylation levels of mTORC1, P70S6K and 4EBP1 by western blot. Furthermore, we used the sulforhodamine B (SRB) and chick chorioallantoic membrane (CAM) assay to analyze cell viability in vitro and in vivo after treatment with ESD activator FPD5. RESULTS: We screened FKBP25 as a candidate protein to interact with ESD by yeast two-hybrid assay. Then we verified the interaction between ESD and endogenous FKBP25 or ectopically expressed GFP-FKBP25 by CO-IP. Moreover, the N-terminus (1-90 aa) domain of FKBP25 served as the crucial element for their interaction. More importantly, ESD reduced the K48-linked poly-ubiquitin chains of FKBP25 and thus stabilized cytoplasmic FKBP25. ESD also promoted FKBP25 to bind more mTORC1, suppressing the activity of mTORC1. In addition, ESD suppressed tumor cell growth in vitro and in vivo through autophagy. CONCLUSIONS: These findings provide novel evidence for elucidating the molecular mechanism of ESD and ubiquitination of FKBP25 to regulate autophagy and cancer cell growth. The ESD/FKBP25/mTORC1 signaling pathway is involved in inhibiting tumor cell growth via regulating autophagy.

Discovery of a fluorescigenic pyrazoline derivative targeting ubiquitin.

Despite significant process in ubiquitin modification by using traditional genetic methods, chemical small molecules that directly target and modify ubiquitin are little reported. Here, we find that a fluorescigenic pyrazoline derivative (FPD5) could do so effectively. Molecule docking revealed that lysine 11 of ubiquitin was the key contact residue. FPD5, with stronger fluorescence, elevated the ubiquitination of beclin 1 (BECN1) and promoted autophagy. This study highlights that targeting ubiquitin by chemical small molecules enables us to modulate ubiquitination and the downstream signaling in the ubiquitin system.

Finding the mechanism of esterase D activation by a small molecule.

People with reduced esterase D (ESD) activity are susceptible to many diseases. However, how to activate ESD is still unknown. To address the question, we identified that 4-chloro-2-(5-phenyl-1-(pyridin-2-yl)-4, 5-dihydro-1H-pyrazol-3-yl) phenol (FPD5) could be a good candidate activator for ESD activity. We found that FPD5 could increase ESD activity in a dose-dependent way. FPD5 bound directly to ESD at Lys180 rather than its ubiquitination site Lys213. Site-directed mutagenesis at the binding site or the ubiquitination site inhibited FPD5 action. FPD5 increased the level of ESD mono-ubiquitination and mutESD K213A completely inhibited this action. Our findings highlighted the activation mechanism of ESD via promoting the mono-ubiquitination of ESD.

Autophagy, Hyperlipidemia, and Atherosclerosis.

Autophagy is an evolutionarily conserved process in eukaryotes that processes the turnover of intracellular substances. Atherosclerosis is a disease caused by multiple factors, it mainly occurs on the walls of large and medium blood vessels and atherosclerotic plaques form in the intima of the blood vessels. Hyperlipidemia is considered to be a very dangerous factor leading to cardiovascular and cerebrovascular diseases, especially atherosclerosis. This chapter mainly introduces the key role of autophagy in hyperlipidemia and atherosclerosis, that is, impaired lipophagy affects the degradation of triacylglycerol, cholesterol, etc., leading to hyperlipidemia in atherosclerosis. In patients, excessive levels of autophagy accelerate the rupture of atherosclerotic plaque. This chapter also describes the advances in the treatment of atherosclerosis and hyperlipidemia by targeted autophagy.

A study about immunomodulatory effect and efficacy and prognosis of human umbilical cord mesenchymal stem cells in patients with chronic hepatitis B-induced decompensated liver cirrhosis.

BACKGROUND AND AIM: The aim of our study was to investigate the immunomodulatory effect and short-term efficacy and long-term prognosis of decompensated liver cirrhosis patients caused by hepatitis B after a double transplantation with human umbilical cord mesenchymal stem cells (hUCMSCs). METHODS: Fifty inpatients were recruited and given the same medical treatments, receiving hUCMSCs injection intravenously. Fifty-three patients (Group B) matched for age, sex, and baseline alanine aminotransferase, aspartate aminotransferase, albumin, total bilirubin, prothrombin time, and model for end-stage liver disease score and Child-Pugh classification, acted as the control group. RESULTS: Interleukin-6 and tumor necrosis factor alpha levels markedly decreased, and interleukin-10 level apparently increased in Group A at 2 and 4 weeks after treatment. Transforming growth factor beta in Group A increased more remarkably at 2 weeks after treatment. T4 cells and Treg cells in Group A were apparently higher than those in Group B at 2 and 4 weeks after treatment, and T8 cells and B cells were significantly lower than those in Group B. Aspartate aminotransferase levels in Group A were dramatically declining at 8 and 12 weeks after treatment. Levels of albumin, total bilirubin, and prothrombin time in Group A were apparently improved from 4 to 12 weeks after treatment. The improvements in model for end-stage liver disease and Child-Pugh scores in Group A were notably superior to those in Group B from 4 to 36 weeks after treatment. There were no remarkable differences in the incidence of developing liver failure throughout the follow-up period, but the mortality rate of Group A was lower than that of Group B. CONCLUSION: This therapeutic method may be an appropriate choice for patients with decompensated liver cirrhosis.

Visualizing the Efimov Correlation in Bose Polarons.

The Bose polaron is a quasiparticle of an impurity dressed by surrounding bosons. In few-body physics, it is known that two identical bosons and a third distinguishable particle can form a sequence of Efimov bound states in the vicinity of interspecies scattering resonance. On the other hand, in the Bose polaron system with an impurity atom embedded in many bosons, no signature of Efimov physics has been reported in the existing spectroscopy measurements to date. In this Letter, we propose that a large mass imbalance between a light impurity and heavy bosons can help produce visible signatures of Efimov physics in such a spectroscopy measurement. Using the diagrammatic approach in the virial expansion to include three-body effects from pair-wise interactions, we determine the impurity self-energy and its spectral function. Taking the ^{6}Li-^{133}Cs system as a concrete example, we find two visible Efimov branches in the polaron spectrum, as well as their hybridizations with the attractive polaron branch. We also discuss the general scenarios for observing the signature of Efimov physics in polaron systems. This work paves the way for experimentally exploring intriguing few-body correlations in a many-body system in the near future.

Three-component ultracold Fermi gases with spin-orbit coupling.

We investigate the pairing physics in a three-component Fermi-Fermi mixture, where a few fermionic impurities are immersed in a noninteracting two-component Fermi gas with synthetic spin-orbit coupling (SOC), and interact attractively with one spin species in the Fermi gas. Because of the interplay of SOC and the spin-selective interaction, the molecular state intrinsically acquires a nonzero center-of-mass momentum, which results in a new type of Fulde-Ferrell (FF) pairing in spin-orbit coupled Fermi systems. The existence of the Fermi sea can also lead to the competition between FF-like molecular states with different center-of-mass momenta, which corresponds to a first-order transition between FF phases in the thermodynamic limit. As the interaction strength is tuned, a polaron-molecule transition occurs in the highly imbalanced system, where the boundary varies nonmonotonically with SOC parameters and gives rise to the reentrance of polaron states. The rich physics in this system can be probed using existing experimental techniques.

Universal trimers induced by spin-orbit coupling in ultracold Fermi gases.

In this Letter we address the issue of how synthetic spin-orbit (SO) coupling can strongly affect three-body physics in ultracold atomic gases. We consider a system which consists of three fermionic atoms, including two spinless heavy atoms and one spin-1/2 light atom subjected to an isotropic SO coupling. We find that SO coupling can induce universal three-body bound states with a negative s-wave scattering length at a smaller mass ratio, where no trimer bound state can exist if in the absence of SO coupling. The energies of these trimers are independent of the high-energy cutoff, and therefore they are universal ones. Moreover, the resulting atom-dimer resonance can be effectively controlled by SO coupling strength. Our results can be applied to systems like a 6Li and 40K mixture.