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Martynoside (MAR) is a bioactive glycoside of Rehmannia glutinosa, a traditional Chinese herb frequently prescribed for treating chemotherapy-induced pancytopenia. Despite its clinical usage in China for thousands of years, the mechanism of MAR's hematopoietic activity and its impact on chemotherapy-induced antitumor activity are still unclear. Here, we showed that MAR protected ex vivo bone marrow cells from 5-fluorouracil (5-FU)-induced cell death and inflammation response by down-regulating the TNF signaling pathway, in which II1b was the most regulatory gene. Besides, using mouse models with melanoma and colon cancer, we further demonstrated that MAR had protective effects against 5-FU-induced myelosuppression in mice without compromising its antitumor activity. Our results showed that MAR increased the number of bone marrow nucleated cells (BMNCs) and the percentage of leukocyte and granulocytic populations in 5-FU-induced myelosuppressive mice, accompanied by an increase in numbers of circulating white blood cells and platelets. The transcriptome profile of BMNCs further showed that the mode of action of MAR might be associated with the increased survival of BMNCs and the improvement of the bone marrow microenvironment. In summary, we revealed the potential molecular mechanism of MAR to counteract 5-FU-induced bone marrow cytotoxicity both ex vivo and in vivo, and highlighted its potential clinical usage in cancer patients experiencing chemotherapy-induced multi-lineage myelosuppression.

RNA viruses, such as hepatitis C virus (HCV), influenza virus, and SARS-CoV-2, are notorious for their ability to evolve rapidly under selection in novel environments. It is known that the high mutation rate of RNA viruses can generate huge genetic diversity to facilitate viral adaptation. However, less attention has been paid to the underlying fitness landscape that represents the selection forces on viral genomes, especially under different selection conditions. Here, we systematically quantified the distribution of fitness effects of about 1,600 single amino acid substitutions in the drug-targeted region of NS5A protein of HCV. We found that the majority of nonsynonymous substitutions incur large fitness costs, suggesting that NS5A protein is highly optimized. The replication fitness of viruses is correlated with the pattern of sequence conservation in nature, and viral evolution is constrained by the need to maintain protein stability. We characterized the adaptive potential of HCV by subjecting the mutant viruses to selection by the antiviral drug daclatasvir at multiple concentrations. Both the relative fitness values and the number of beneficial mutations were found to increase with the increasing concentrations of daclatasvir. The changes in the spectrum of beneficial mutations in NS5A protein can be explained by a pharmacodynamics model describing viral fitness as a function of drug concentration. Overall, our results show that the distribution of fitness effects of mutations is modulated by both the constraints on the biophysical properties of proteins (i.e., selection pressure for protein stability) and the level of environmental stress (i.e., selection pressure for drug resistance). IMPORTANCE Many viruses adapt rapidly to novel selection pressures, such as antiviral drugs. Understanding how pathogens evolve under drug selection is critical for the success of antiviral therapy against human pathogens. By combining deep sequencing with selection experiments in cell culture, we have quantified the distribution of fitness effects of mutations in hepatitis C virus (HCV) NS5A protein. Our results indicate that the majority of single amino acid substitutions in NS5A protein incur large fitness costs. Simulation of protein stability suggests viral evolution is constrained by the need to maintain protein stability. By subjecting the mutant viruses to selection under an antiviral drug, we find that the adaptive potential of viral proteins in a novel environment is modulated by the level of environmental stress, which can be explained by a pharmacodynamics model. Our comprehensive characterization of the fitness landscapes of NS5A can potentially guide the design of effective strategies to limit viral evolution.

Yellow leaf disease caused by sugarcane yellow leaf virus (SCYLV) is one of the most prevalent diseases worldwide. In this study, six near-complete genome sequences of SCYLV were determined to be 5775–5881 bp in length. Phylogenetic analysis revealed that the two SCYLV isolates from Réunion Island, France, and four from China were clustered into REU and CUB genotypes, respectively, based on 50 genomic sequences (this study = 6, GenBank = 44). Meanwhile, all 50 isolates were clustered into three phylogroups (G1–G3). Twelve significant recombinant events occurred in intra- and inter-phylogroups between geographical origins and host crops. Most recombinant hotspots were distributed in coat protein read-through protein (RTD), followed by ORF0 (P0) and ORF1 (P1). High genetic divergences of 12.4% for genomic sequences and 6.0–24.9% for individual genes were determined at nucleotide levels. The highest nucleotide diversity (π) was found in P0, followed by P1 and RdRP. In addition, purifying selection was a main factor restricting variability in SCYLV populations. Infrequent gene flow between Africa and the two subpopulations (Asia and America) were found, whereas frequent gene flow between Asia and America subpopulations was observed. Taken together, our findings facilitate understanding of genetic diversity and evolutionary dynamics of SCYLV.

The pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has brought an unprecedented impact upon the global economy and public health. Although the SARS-CoV-2 virology has been gradually investigated, measures to combat this new threat in public health are still absent. To date, no certificated drug or vaccine has been developed for the treatment or prevention of coronavirus disease Extensive researches and international coordination has been conducted to rapidly develop novel vaccines against SARS-CoV-2 pandemic. Several major breakthroughs have been made through the identification of the genetic sequence and structural/non-structural proteins of SARS-CoV-2, which enabled the development of RNA-, DNA-based vaccines, subunit vaccines, and attenuated viral vaccines. In this review article, we present an overview of the recent advances of SARS-CoV-2 vaccines and the challenges that may be encountered in the development process, highlighting the advantages and disadvantages of these approaches that may help in effectively countering COVID-19.

Based on the monitoring data of the Guangdong-Hong Kong-Macao Pearl River Delta Regional (PRD) Air Quality Monitoring Network from 2006 to 2019, the ozone trend in RRD was analyzed using the Mann-Kendall test method, Sen's slope method, and the Pettitt change point test. The results show that:① the average ozone concentration in the PRD has increased significantly from 2006 to 2019 (

The pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has brought an unprecedented impact upon the global economy and public health. Although the SARS-CoV-2 virology has been gradually investigated, measures to combat this new threat in public health are still absent. To date, no certificated drug or vaccine has been developed for the treatment or prevention of coronavirus disease Extensive researches and international coordination has been conducted to rapidly develop novel vaccines against SARS-CoV-2 pandemic. Several major breakthroughs have been made through the identification of the genetic sequence and structural/non-structural proteins of SARS-CoV-2, which enabled the development of RNA-, DNA-based vaccines, subunit vaccines, and attenuated viral vaccines. In this review article, we present an overview of the recent advances of SARS-CoV-2 vaccines and the challenges that may be encountered in the development process, highlighting the advantages and disadvantages of these approaches that may help in effectively countering COVID-19.

Vaccines based on live attenuated viruses often induce broad, multifaceted immune responses. However, they also usually sacrifice immunogenicity for attenuation. It is particularly difficult to elicit an effective vaccine for herpesviruses due to an armament of immune evasion genes and a latent phase. Here, to overcome the limitation of attenuation, we developed a rational herpesvirus vaccine in which viral immune evasion genes were deleted to enhance immunogenicity while also attaining safety. To test this vaccine strategy, we utilized murine gammaherpesvirus-68 (MHV-68) as a proof-of-concept model for the cancer-associated human γ-herpesviruses, Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus. We engineered a recombinant MHV-68 virus by targeted inactivation of viral antagonists of type I interferon (IFN-I) pathway and deletion of the latency locus responsible for persistent infection. This recombinant virus is highly attenuated with no measurable capacity for replication, latency, or persistence in immunocompetent hosts. It stimulates robust innate immunity, differentiates virus-specific memory T cells, and elicits neutralizing antibodies. A single vaccination affords durable protection that blocks the establishment of latency following challenge with the wild type MHV-68 for at least six months post-vaccination. These results provide a novel approach to effective vaccination against cancer-associated herpesviruses through the elimination of latency and key immune evasion mechanisms from the pathogen.

Carbapenem-resistant Acinetobacter nosocomialis (CRAn) is a significant public health concern. Tigecycline non-susceptible CRAn (Tn-CRAn) isolates have emerged worldwide. Tigecycline resistance is mainly related to the overexpression of AdeABC efflux pump controlled by AdeRS two-component system (TCS). Two novel tetracycline derivatives, omadacycline and eravacycline, may present a treatment option for CRAn. This study investigated the in vitro antimicrobial activity of tigecycline, omadacycline and eravacycline against clinical CRAn isolates and the contribution of efflux pumps in their resistance. Eighty-nine clinical CRAn isolates, including 57 Tn-CRAn isolates were evaluated for minimum inhibitory concentrations (MICs) by the broth microdilution. The relationship between the antimicrobial resistance and efflux pump expression was assessed by their responses to the efflux pump inhibitor 1-(1-naphthylmethyl)-piperazine (NMP). The contribution of the AdeABC efflux pump in their resistance was determined by the complementation of the AdeRS two-component system in wild-type, adeRS operon and adeB gene knockout strains. Among the 89 isolates, omadacycline and eravacycline MICs were correlated closely with those of tigecycline. They demonstrated improved potency, based on MIC90 values, by showing a 4 to 8-fold greater potency than tigecycline. The synergetic effects of tigecycline, omadacycline and eravacycline with NMP were observed in 57 (100%), 13 (22.8%), and 51 (89.5%) of Tn-CRAn isolates, respectively. Further analysis showed that the laboratory strain carrying the Type 1 adeRS operon increased the tigecycline, omadacycline and eravacycline MICs by 4-8-folds, respectively. Eravacycline demonstrated improved potency over tigecycline against populations of CRAn, including Tn-CRAn isolates. The over-expression of AdeABC efflux pumps was directly activated by the AdeRS two-component system and simultaneously reduced the susceptibilities of tigecycline, eravacycline, and omadacycline. Omadacycline and eravacycline MICs were correlated closely with those of eravacycline.

COVID-19 pandemic is the third zoonotic coronavirus (CoV) outbreak of the century after severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome (MERS) since 2012. Treatment options for CoVs are largely lacking. Here, we show that clofazimine, an anti-leprosy drug with a favorable safety and pharmacokinetics profile, possesses pan-coronaviral inhibitory activity, and can antagonize SARS-CoV-2 replication in multiple in vitro systems, including the human embryonic stem cell-derived cardiomyocytes and ex vivo lung cultures. The FDA-approved molecule was found to inhibit multiple steps of viral replication, suggesting multiple underlying antiviral mechanisms. In a hamster model of SARS-CoV-2 pathogenesis, prophylactic or therapeutic administration of clofazimine significantly reduced viral load in the lung and fecal viral shedding, and also prevented cytokine storm associated with viral infection. Additionally, clofazimine exhibited synergy when administered with remdesivir. Since clofazimine is orally bioavailable and has a comparatively low manufacturing cost, it is an attractive clinical candidate for outpatient treatment and remdesivir-based combinatorial therapy for hospitalized COVID-19 patients, particularly in developing countries. Taken together, our data provide evidence that clofazimine may have a role in the control of the current pandemic SARS-CoV-2, endemic MERS-CoV in the Middle East, and, possibly most importantly, emerging CoVs of the future.

The research progress of acupuncture analgesia in recent years is analyzed to summarize the analgesic mechanism of acupuncture on neuropathic pain. The analgesic mechanism of acupuncture on neuropathic pain is discussed from peripheral level and central level, including peripheral sensitization and immune inflammatory response, changes of ion channel, central sensitization, regulation of cell signal pathway, activation of spinal glial cells, etc. It is suggested that the focus of future research should include conducting in-vitro studies with the help of multi-omics technology to detect the changes of metabolic substances and signal pathway molecules in patients with neuropathic pain before and after acupuncture to further clarify the mechanism of acupuncture analgesia.

To compare the therapeutic effects of "Bangci"(focal center-side needling) and encircling needling in promoting skin wound healing and local blood perfusion in diabetic mice.Thirty-two male C57BL/6N mice were randomized into normal, diabetic model, focal center-side needling and encircling needling groups (The wound shrinkage rates were significantly higher at the time-points of 3, 5, 7, 9 and 11 d after modeling in both focal center-side needling and encircling needling groups than in the model group (Both focal center-side needling and encircling needling can promote the skin wound healing by increasing the blood perfusion in diabetic mice, and the therapeutic effect of the encircling needling method was significantly superior to that of the focal center-side needling method.

The Coronavirus‐2019 (COVID‐19) pandemic has put tremendous strain on healthcare systems worldwide. It is challenging for clinicians to differentiate COVID‐19 from other acute respiratory tract infections via clinical symptoms because those who are infected display a wide range of symptoms. An effective, point‐of‐care (POC) diagnostic tool could mitigate healthcare system strain, protect healthcare professionals, and support quarantine efforts. We believe that a POC tool can be developed that would be rapid, easy to use, and inexpensive. It could be used in the home, in resource‐limited areas, and even in clinical settings. In this article, we summarize the current state of COVID‐19 diagnostic methods and make a case for an all‐in‐one, highly sensitive POC assay that integrates antibody detection, protein detection, and serum cytokine detection to diagnose COVID‐19 infection. We believe this article will provide insights into the current state of diagnostics for COVID‐19, and promote additional research and tool development that could be exceptionally impactful.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a threat to global public health. Prompt patient identification and quarantine is the most effective way to control its rapid transmission, which can be facilitated by early detection of viral antigens. Here we present a platform to develop and optimize the fibronectin-based affinity-enhanced antibody mimetics (monobodies) for recognizing viral antigens. Specifically, we developed monobodies targeting SARS-CoV-2 nucleocapsid (N) protein. We showed that two monobodies, NN2 and NC2, bind to N protein’s N- and C-terminal domains respectively with a Kd in nM range.The specificity of the recognition was confirmed with co-immunoprecipitation and immunofluorescence assays. Furthermore, we demonstrated that one round of in vitro maturation using mRNA display can improve the binding affinity of monobodies. Machine learning algorithms were integrated with deep sequencing data for selecting candidates that improve the detection sensitivity of N. Using this pair of monobodies, we have developed an enzyme-linked immunosorbent assay (ELISA) for viral detection. We were able to detect recombinant N at 4 pg/ml and detect N in viral culture supernatant, with no cross-reactivity with other CoV. Integrating high-dense mutagenesis, mRNA display, deep sequencing and machine learning, this platform can be applied through iterations to identify and optimize monobodies against emerging viral antigens, potentiating point-of-care detection of communicable diseases in a cost-and time-sensitive manner.Authors Yushen Du, Tian-hao Zhang, Xiangzhi Meng, Yuan Shi, and Menglong Hu contributed equally to this work.

The emergence of novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19). To date, more than 2.1 million confirmed cases and 139,500 deaths have been reported worldwide, and there are currently no medical countermeasures available to prevent or treat the disease. As the development of a vaccine could require at least 12-18 months, and the typical timeline from hit finding to drug registration of an antiviral is >10 years, repositioning of known drugs can significantly accelerate the development and deployment of therapies for COVID-19. To identify therapeutics that can be repurposed as SARS-CoV-2 antivirals, we profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules. Here, we report the identification of 30 known drugs that inhibit viral replication. Of these, six were characterized for cellular dose-activity relationships, and showed effective concentrations likely to be commensurate with therapeutic doses in patients. These include the PIKfyve kinase inhibitor Apilimod, cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO 5334, and the CCR1 antagonist MLN-3897. Since many of these molecules have advanced into the clinic, the known pharmacological and human safety profiles of these compounds will accelerate their preclinical and clinical evaluation for COVID-19 treatment.

Zika virus (ZIKV) is a major human pathogen. ZIKV can replicate in female and male reproductive organs, thus facilitating the human-human transmission cycle. Viral shedding in the semen can increase the risk of ZIKV transmission through sexual mode. Therefore, the vaginal and anorectal mucosa are relevant sites for ZIKV infection. However, the pathobiology of ZIKV transmission through the rectal route is not well understood. Here, we utilize a mouse model system to investigate the immunopathological consequences following ZIKV infection of the rectal mucosa compared to a subcutaneous route of infection. We show that ZIKV-rectal inoculation results in viremia with subclinical infection. ZIKV infects the mucosal epithelium and submucosal dendritic cells, inducing immune and inflammatory cell infiltration. Rectal transmission of ZIKV resulted in the generation of serum-neutralizing antibody responses. Mass cytometry analyses of splenocytes showed a significantly reduced level of inflammatory monocyte and neutrophil cellular responses in the rectal route group. Furthermore, immunological priming through the rectal mucosa with an attenuated ZIKV strain resulted in significant protection from lethal subcutaneous ZIKV challenge, further eliciting robust memory CD4-positive (CD4(+)) and CD8(+) T-cell and ZIKV-specific serum-neutralizing antibody responses. Thus, our study provides deeper immunopathobiological insights on rectal transmission and highlights a rational strategy for mucosal immunization. This model system recapitulates clinical aspects of human ZIKV disease outcome, where most infections are well controlled and result in subclinical and asymptomatic outcomes. IMPORTANCE Zika virus is a clinically significant human pathogen that is primarily transmitted and spread by Aedes species mosquitoes but is also sexually transmissible. The recent pandemic in the Americas led to an unprecedented increase of newborn babies with developmental brain and eye abnormalities. To date, there is no licensed vaccine or therapeutic intervention available for the fight against ZIKV. Understanding the sexual transmission of ZIKV through vaginal and rectal routes is necessary to restrict virus transmission and spread. This study examines the early immunological and pathological consequences of rectal and subcutaneous routes of ZIKV infection using a mouse model. We characterized the primary target cells of ZIKV infection and the subsequent mucosal immune responses to infection, and we demonstrate the protective effect of mucosal rectal immunization using an attenuated ZIKV strain. This mucosal vaccination approach can be further developed to prevent future ZIKV outbreaks.

Summary HIV latency prevents cure of infection with antiretroviral therapy (ART) alone. One strategy for eliminating latently infected cells involves the induction of viral protein expression via latency-reversing agents (LRAs), allowing killing of host cells by viral cytopathic effects or immune effector mechanisms. Here, we combine a barcoded HIV approach and a humanized mouse model to study the effects of a designed, synthetic protein kinase C modulating LRA on HIV rebound. We show that administration of this compound during ART results in a delay in rebound once ART is stopped. Furthermore, the rebounding virus appears composed of a smaller number of unique barcoded viruses than occurs in control-treated animals, suggesting that some reservoir cells that would have contributed virus to the rebound process are eliminated by LRA administration. These data support the use of barcoded virus to study rebound and suggest that LRAs may be useful in HIV cure efforts., Graphical Abstract, Highlights A genetically barcoded HIV swarm has been constructed and characterized This swarm forms a latent reservoir in antiretroviral (ART)-treated humanized mice Administering an HIV latency-reversing agent (LRA) during ART delays rebound LRA administration during ART also reduces barcode diversity of rebounding virus, Marsden et al. construct a barcoded HIV swarm to study HIV latency formation and rebound in humanized mice. They find that the administration of a PKC modulating HIV latency-reversing agent delays rebound and reduces the genetic diversity of rebounding virus when antiretroviral therapy is stopped, suggesting the reduction of the reservoir.

Antimicrobial-resistant (AMR) bacterial infections, including those caused by Acinetobacter baumannii, have emerged as a clinical crisis worldwide. Immunization with AMR determinants has been suggested as a novel approach to combat AMR bacteria, but has not been validated. The present study targeted tigecycline (TGC) resistance determinants in A. baumannii to test the feasibility of this approach. Using bioinformatic tools, four candidates, AdeA, AdeI, AdeK, and TolC, belonging to the resistance-nodulation-division (RND) efflux pump were identified as highly conserved and exposed antigens from 15 A. baumannii genomes. Antisera generated from recombinant proteins showed the capability to reserve Hoechst 33342, a substrate of the efflux pump, in bacterial cells. The rTolC antisera had the highest complement-dependent killing and opsonophagocytosis effect compared to the sera from phosphate-buffered saline immunized mice. Among the antisera, anti-rAdeK-specific antisera decreased the minimal inhibitory concentration of TGC in 26.7% of the tested isolates. Immunization with rAdeK significantly potentiated TGC efficacy in treating TGC-resistant A. baumannii pneumonia in the murine model. The bacterial load (7.5 × 105 vs. 3.8 × 107, p < 0.01) and neutrophil infiltration in the peri-bronchial vasculature region of immunized mice was significantly lower compared to the PBS-immunized mice when TGC was administrated concomitantly. Collectively, these results suggest that active immunization against resistance determinants might be a feasible approach to combat multidrug-resistant pathogens in high risk population.

The bacterial flagellar motor (BFM) is a rotary electric nanomachine that drives swimming in a wide variety of bacterial species. There have been many milestones, both theoretical and experimental, that have furthered our understanding of this tiny motor since the first swimming flagellated bacteria was observed. In this article, we review some of these key events, and illustrate how theory and experiment intertwine and inform each other towards a deeper understanding of the BFM’s mechanism. Experimental results have inspired theoreticians to build and update models, while model predictions have served to guide experimental design. This cooperative and mutually beneficial communication is a prime example of the interdisciplinary and open nature of modern scientific research.

As the first discovered human cancer virus, Epstein–Barr virus (EBV) causes Burkitt’s lymphoma and nasopharyngeal carcinoma. Isolating virions for determining high-resolution structures has been hindered by latency—a hallmark of EBV infection—and atomic structures are thus available only for recombinantly expressed EBV proteins. In the present study, by symmetry relaxation and subparticle reconstruction, we have determined near-atomic-resolution structures of the EBV capsid with an asymmetrically attached DNA-translocating portal and capsid-associated tegument complexes from cryogenic electron microscopy images of just 2,048 EBV virions obtained by chemical induction. The resulting atomic models reveal structural plasticity among the 20 conformers of the major capsid protein, 2 conformers of the small capsid protein (SCP), 4 conformers of the triplex monomer proteins and 2 conformers of the triplex dimer proteins. Plasticity reaches the greatest level at the capsid–tegument interfaces involving SCP and capsid-associated tegument complexes (CATC): SCPs crown pentons/hexons and mediate tegument protein binding, and CATCs bind and rotate all five periportal triplexes, but notably only about one peri-penton triplex. These results offer insights into the EBV capsid assembly and a mechanism for recruiting cell-regulating factors into the tegument compartment as ‘cargoes’, and should inform future anti-EBV strategies. This study reveals features of Epstein–Barr virus that are similar but not identical to the closely related Kaposi’s sarcoma-associated herpesvirus. The authors provide locations of protein components within the viral capsid and reveal different conformers of protein components by revealing variations in links between capsid proteins and exploiting approaches with relaxation of symmetry. The capsid-associated tegument complex is loaded on to the capsid with long-range asymmetry, relative to the location of the portal vertex (the site of genome entry and egress).

For potential military applications, a flexible metamaterial absorber (MMA) working on whole K-bands with total-thickness of 3.367 mm, ultra-broadband, polarization-insensitive, and wide-angle stability is presented based on frequency-selective surface (FSS). The absorber is composed of polyvinyl chloride (PVC) layer, polyimide (PI) layer, and poly tetra fluoro ethylene (PTFE) layer, with a sandwich structure of PVC–PI–PTFE–metal plate. Periodic conductive patterns play a crucial role in the absorber, and in traditional, it is designed on the upper surface of PI layer to form LC resonance. Different from commonly absorber, all the patterns are located on the lower surface of the PI layer in this work, and hence the impedance matching and absorptivity are improved in this purposed absorber. The flexible absorber with patterns on lower surface of the PI layer is compared with that on upper surface of the PI layer, the difference and the reasons are explained by absorption mechanism based on equivalent circuit model, and surface current density and electric field distribution are used to analyze resonance peaks. Absorptivity is greater than 90% in a frequency range of 10.47 GHz–45.44 GHz with relative bandwidth of 125.1%, covering the whole Ku, K, Ka, and some of X, U bands, especially containing the whole K bands from 12 GHz to 40 GHz. Radar cross section (RCS) is reduced at least 10 dB in 11.48 GHz–43.87 GHz frequency ranges, and absorption remained about 90% when the incident angle changed from 0 ° to 55°. The purposed absorber is fabricated, measured, and experiment results show good agreement with theoretical analysis and numerical simulation. After bonded on outer surface of different cylinders with diameters of 200 mm and 100 mm, the absorption of MMA is approximately reduced 10% and 20% respectively, which shows good conformal character with surface of various curvatures. Due to the attractive performance on strong absorption in the whole K-bands, flexible and easy conformal, our design exhibits broad potential application in radar stealth and sensors.

To enhance device performance and reduce fabrication cost, a series of electron transporting material (ETM)-free perovskite solar cells (PSCs) is developed by TCAD Atlas. The accuracy of the physical mode of PSCs is verified, due to the simulations of PEDOT:PSS–CH3NH3PbI3–PCBM and CuSCN–CH3NH3PbI3–PCBM p–i–n PSCs showing a good agreement with experimental results. Different hole transporting materials (HTMs) are selected and directly combined with n-CH3NH3PbI3, and the CuSCN–CH3NH3PbI3 is the best in these ETM-free PSCs. To further study the CuSCN–CH3NH3PbI3 PSC, the influences of back electrode material, gradient band gap, thickness, doping concentration, and bulk defect density on the performance are investigated. Energy band and distribution of electric field are utilized to optimize the design. As a result, the efficiency of CuSCN–CH3NH3PbI3 PSC is achieved to be 26.64%. This study provides the guideline for designing and improving the performances of ETM-free PSCs.

Let G be a graph and k ≥ 2 a positive integer. Let h: E(G) → [0, 1] be a function. If $$\sum\limits_{e \mathrel\backepsilon x} {h(e) = k} $$ holds for each x ∈ V (G), then we call G[Fh] a fractional k-factor of G with indicator function h where Fh = {e ∈ E(G): h(e) > 0}. A graph G is fractional independent-set-deletable k-factor-critical (in short, fractional ID-k-factor-critical), if G − I has a fractional k-factor for every independent set I of G. In this paper, we prove that if n ≥ 9k − 14 and for any subset X ⊂ V (G) we have $${N_G}(X) = V(G)if|X| \geqslant \left\lfloor {\frac{{kn}}{{3k - 1}}} \right\rfloor ;or|{N_G}(X)| \geqslant \frac{{3k - 1}}{k}|X|if|X| < \left\lfloor {\frac{{kn}}{{3k - 1}}} \right\rfloor ,$$ then G is fractional ID-k-factor-critical.

Summary: Zika virus (ZIKV) infection causes Guillain-Barré syndrome and severe birth defects. ZIKV envelope (E) protein is the major viral protein involved in cell receptor binding and entry and is therefore considered one of the major determinants in ZIKV pathogenesis. Here we report a gene-wide mapping of functional residues of ZIKV E protein using a mutant library, with changes covering every nucleotide position. By comparing the replication fitness of every viral mutant between mosquito and human cells, we identified that mutations affecting glycosylation display the most divergence. By characterizing individual mutants, we show that ablation of glycosylation selectively benefits ZIKV infection of mosquito cells by enhancing cell entry, whereas it either has little impact on ZIKV infection on certain human cells or leads to decreased infection through the entry factor DC-SIGN. In conclusion, we define the roles of individual residues of ZIKV envelope protein, which contribute to ZIKV replication fitness in human and mosquito cells. : Entomology; Genomics; Virology; Protein Structure Aspects Subject Areas: Entomology, Genomics, Virology, Protein Structure Aspects

Avoiding interferon avoidance Interferon (IFN) expression is a mammal's first response to viral infection. Many viruses have thus evolved mechanisms to evade IFN. Du et al. developed a method to systematically ablate IFN evasion genes from live, attenuated influenza virus (see the Perspective by Teijaro and Burton). A combination of mutants was assembled to construct a virus that triggered transient IFN responses in mice but that was unable to replicate effectively. The transient IFN responses led to robust antibody and memory responses that protected against subsequent challenge with different influenza viruses. This approach could be adapted to improve other RNA virus vaccines. Science , this issue p. 290 ; see also p. 277

Kaposi's sarcoma-associated herpesvirus (KSHV) causes Kaposi's sarcoma, a cancer that commonly affects patients with AIDS and which is endemic in sub-Saharan Africa. The KSHV capsid is highly pressurized by its double-stranded DNA genome, as are the capsids of the eight other human herpesviruses. Capsid assembly and genome packaging of herpesviruses are prone to interruption and can therefore be targeted for the structure-guided development of antiviral agents. However, herpesvirus capsids-comprising nearly 3,000 proteins and over 1,300 Å in diameter-present a formidable challenge to atomic structure determination and functional mapping of molecular interactions. Here we report a 4.2 Å resolution structure of the KSHV capsid, determined by electron-counting cryo-electron microscopy, and its atomic model, which contains 46 unique conformers of the major capsid protein (MCP), the smallest capsid protein (SCP) and the triplex proteins Tri1 and Tri2. Our structure and mutagenesis results reveal a groove in the upper domain of the MCP that contains hydrophobic residues that interact with the SCP, which in turn crosslinks with neighbouring MCPs in the same hexon to stabilize the capsid. Multiple levels of MCP-MCP interaction-including six sets of stacked hairpins lining the hexon channel, disulfide bonds across channel and buttress domains in neighbouring MCPs, and an interaction network forged by the N-lasso domain and secured by the dimerization domain-define a robust capsid that is resistant to the pressure exerted by the enclosed genome. The triplexes, each composed of two Tri2 molecules and a Tri1 molecule, anchor to the capsid floor via a Tri1 N-anchor to plug holes in the MCP network and rivet the capsid floor. These essential roles of the MCP N-lasso and Tri1 N-anchor are verified by serial-truncation mutageneses. Our proof-of-concept demonstration of the use of polypeptides that mimic the smallest capsid protein to inhibit KSHV lytic replication highlights the potential for exploiting the interaction hotspots revealed in our atomic structure to develop antiviral agents.

Background: Automated peritoneal dialysis (APD) can cater to individual needs, provide treatment while asleep, take into account the adequacy of dialysis, and improve the quality of life. Currently, independent research and development of APD machines made in China are more conducive to patients. A randomized, multicenter, crossover study was conducted by comparing an APD machine made in China with an imported machine. The safety, effectiveness, and manipulability of the two machines were compared. Methods: Two hundred and sixty patients who underwent peritoneal dialysis (PD) on a regular basis in 18 centers between August 2015 and February 2016 were included. The inclusion criteria include age ≥18 years and PD ≥30 days. The exclusion criteria were as follows: hemodialysis; exit site or tunnel infection; and peritonitis ≤30 days. The patients were randomly divided into Group A, who were first treated with a FM machine made in China, then changed to an imported machine; and Group B, who were treated using the reverse sequence. APD treatment was performed with 10 L/10 h and 5 cycles of exchange. After 72 h, the daily peritoneal Kt/V, the accuracy of the injection rate, accuracy of the injection temperature, safety, and manipulability of the machine were assessed. Noninferiority test was conducted between the two groups. Results: The daily peritoneal Kt/V in the APD machine made in China and the imported APD machine were 0.17 (0.14, 0.25) and 0.16 (0.13, 0.23), respectively. There was no significant difference between the groups (Z = 0.15, P = 0.703). The lower limit of the daily Kt/V difference between the two groups was 0.0069, which was greater than the noninferiority value of −0.07 in this study. The accuracy of the injection rate and injection temperature was 89.7% and 91.5%, respectively, in the domestic APD machine, which were both slightly better than the accuracy rates of 84.0% and 86.8% in the imported APD machine (89.7% vs. 84.0%, P = 0.2466; 91.5% vs. 86.8%, P = 0.0954). Therefore, the APD machine made in China was not inferior to the imported APD machine. The fuselage of the imported APD machine was space-saving, while the APD machine made in China was superior with respect to body mobility, man-machine dialog operation, alarm control, and patient information recognition. Conclusions: The FM machine made in China was not inferior to the imported APD machine. In addition, the FM machine made in China had better operability. Trial Registration: Clinicaltrials.gov, NCT02525497; https://clinicaltrials.gov/ct2/results?cond=&term=NCT02525497&cntry=& state=&city=&dist=.

Background: The Beijing lineage of Mycobacterium tuberculosis (MTB) is the most predominant MTB strain in Asian countries and is spreading worldwide, however, the East AfricanâIndian (EAI) lineage is also particularly prevalent in many tropical Asian countries. The evolutionary relationships among MTB EAI isolates from Taiwan and those of tropical Asian countries remain unknown. Methods: The EAI strains collected from patients in Taiwan were analyzed using spacer oligonucleotide typing and mycobacterial interspersed repetitive unitâvariable number of tandem repeats (MIRU-VNTR) typing, and compared with published profiles from Cambodia and Singapore to investigate potential epidemiological linkages. Results: Among the three countries, the EAI lineage was most prevalent in Cambodia (60%; Singapore, 25.62%; and Taiwan, 21.85%), having also the highest rates of multidrug resistance and lowest rates of clustering of MTB isolates. We describe a convenient method using seven selected MIRU-VNTR loci for first-line typing to discriminate Beijing and EAI lineages. A potential epidemiological linkage in these tropical Asian countries is also discussed based on a minimum-spanning tree constructed using 24 MIRU-VNTR loci of MTB EAI strains. Conclusion: This study identified evolutionary relationships among MTB EAI isolates from Taiwan and those of two other tropical Asian countries, Cambodia and Singapore. Keywords: East AfricanâIndian family, Mycobacterium tuberculosis, tropical Asian countries

This study investigated the morphologies of the intermetallic compounds (IMC) formed during soldering reaction between Sn1.0Ag0.7Cu–1.0SnO2 composite solder and Cu substrate at various temperatures. The prism-type Cu6Sn5 forms when the soldering temperature is 260 or 280 °C, while those grains transform from prism type to scallop type at the temperatures of 300 and 320 °C. It can be found that the morphologies of Cu6Sn5 grains affect adsorption of Ag3Sn nanoparticles during soldering reaction. The scallop-type grains with a higher growth rate need to adsorb large amounts of Ag3Sn particles. In terms of mechanical behavior, the shear strength of solder joint is improved from 40 to 46 MPa at soldering temperature of 300 °C. In addition, the thickness of IMC increases with the extension of aging time. During aging, the morphology of Cu6Sn5 grains remains scallop type, but the number of Ag3Sn nanoparticles is reduced largely. The scallop-type Cu6Sn5 can increase in size and flatten in morphology with the aging time increasing. When the soldering temperature changes from 260 to 360 °C, the morphologies of Cu6Sn5 grains transformed from prism-type to scallop-type. The shear strength of solder joint is improved from 40 to 46 Mpa at 300 °C soldering temperature

Summary: The human cerebral cortex possesses distinct structural and functional features that are not found in the lower species traditionally used to model brain development and disease. Accordingly, considerable attention has been placed on the development of methods to direct pluripotent stem cells to form human brain-like structures termed organoids. However, many organoid differentiation protocols are inefficient and display marked variability in their ability to recapitulate the three-dimensional architecture and course of neurogenesis in the developing human brain. Here, we describe optimized organoid culture methods that efficiently and reliably produce cortical and basal ganglia structures similar to those in the human fetal brain in vivo. Neurons within the organoids are functional and exhibit network-like activities. We further demonstrate the utility of this organoid system for modeling the teratogenic effects of Zika virus on the developing brain and identifying more susceptibility receptors and therapeutic compounds that can mitigate its destructive actions. : Cerebral organoids recapitulate many aspects of human corticogenesis and are a useful platform for modeling neurodevelopmental mechanisms and diseases. Watanabe et al. describe enhanced organoid methods and model ZIKV pathology. More susceptibility receptors for ZIKV are identified, and differential effects of various compounds to mitigate ZIKV-induced cytopathy are demonstrated. Keywords: neurogenesis, neural stem cell, embryonic stem cell, organoid, differentiation, neural development, cerebral cortex, Zika virus, human brain

Despite full immunoprophylaxis, mother-to-child transmission (MTCT) of Hepatitis B Virus still occurs in approximately 2–5% of HBsAg positive mothers. Little is known about the bottleneck of HBV transmission and the evolution of viral quasispecies in the context of MTCT. Here we adopted a newly developed tag linkage deep sequencing method and analyzed the quasispecies of four MTCT pairs that broke through immunoprophylaxis. By assigning unique tags to individual viral sequences, we accurately reconstructed HBV haplotypes in a region of 836 bp, which contains the major immune epitopes and drug resistance mutations. The detection limit of minor viral haplotypes reached 0.1% for individual patient sample. Dominance of “a determinant” polymorphisms were observed in two children, which pre-existed as minor quasispecies in maternal samples. In all four pairs of MTCT samples, we consistently observed a significant overlap of viral haplotypes shared between mother and child. We also demonstrate that the data can be potentially useful to estimate the bottleneck effect during HBV MTCT, which provides information to optimize treatment for reducing the frequency of MTCT.

Background Saccharum species such as sugarcane and energy cane are key players in the expanding bioeconomy for sugars, bioenergy, and production of high-value proteins. Genomic tools such as culm-regulated promoters would be of great value in terms of improving biomass characteristics through enhanced carbon metabolism for sugar accumulation and/or fiber content for biofuel feedstock. Unlike the situation in dicots, monocot promoters currently used are limited and mostly derived from highly expressed constitutive plant genes and viruses. In this study, a novel promoter region of Sugarcane bacilliform virus (SCBV; genus Badnavirus, family Caulimoviridae), SCBV21 was cloned and mapped by deletion analysis and functionally characterized transiently in monocot and dicot species and stably in sugarcane. Results In silico analysis of SCBV21 [1816 base pair (bp)] identified two putative promoter regions (PPR1 and PPR2) with transcription start sites (TSS1 and TSS2) and two TATA-boxes (TATAAAT and ATATAA), and several vascular-specific and regulatory elements. Deletion analysis revealed that the 710 bp region spanning PPR2 (with TSS2 and ATATAA) at the 3′ end of SCBV21 retained the full promoter activity in both dicots and monocots, as shown by transient expression of the enhanced yellow fluorescent protein (EYFP) gene. In sugarcane young leaf segments, SCBV21 directed a 1.8- and 2.4-fold higher transient EYFP expression than the common maize ubiquitin 1 (Ubi1) and Cauliflower mosaic virus 35S promoters, respectively. In transgenic sugarcane, SCBV21 conferred a preferential expression of the β-glucuronidase (GUS) gene in leaves and culms and specifically in the culm storage parenchyma surrounding the vascular bundle and in vascular phloem cells. Among the transgenic events and tissues characterized in this study, the SCBV21 promoter frequently produced higher GUS activity than the Ubi1 or 35S promoters in a manner that was not obviously correlated with the transgene copy number. Conclusions The newly developed plant viral SCBV21 promoter is distinct from the few existing SCBV promoters in its sequence and expression pattern. The potential of SCBV21 as a tissue-regulated promoter with a strong activity in the culm vascular bundle and its storage parenchyma makes it useful in sugarcane engineering for improved carbon metabolism, increased bioenergy production, and enhanced stress tolerance. Electronic supplementary material The online version of this article (doi:10.1186/s13068-017-0850-9) contains supplementary material, which is available to authorized users.

Objective To observe the effect of scalp acupuncture on the treatment of children with cerebral palsy (CP). Methods Thirty-six children in the USA with cerebral palsy were treated with Chinese scalp acupuncture at the Neuroacupuncture Institute in Santa Fe, New Mexico, USA. Foot motor and sensory area, motor area, speech I area, speech II area, balance area, vision area, apraxia area, and I vision area were selected base on patient's clinical manifestation. Rotating manual stimulation was performed during each session of acupuncture. The retention of needles was 30 minutes. Results These 36 patients received between 3–20 treatments, 5 had complete resolution of their symptom, 14 cases a marked effect, 14 had some effect, and 3 patients experienced no improvement. No adverse events were reported. Conclusion Chinese scalp acupuncture in these 33 cases appears to be an effective treatment for patients with CP and should be considered as an adjunctive therapy for more CP patients. Chinese scalp acupuncture relieved many of these patients' symptoms, increased their quality of life, and reversed many physical disabilities. Some of the patients returned to a normal life. Those treatments have laid a foundation for research into the clinical application of Chinese scalp acupuncture in the treatment of CP.

The energy-based Lagrangian expressions for multiple deforming bodies translating and rotating through an inviscid fluid in the gravity field are proved to be equal to the momentum-type ones This implies that the energy description can be directly adopted to predict dynamic behaviors of these deforming bodies without adding the body deformation thrust to fluid as the generalized force of the body–fluid system although the total mechanical energy of the system is continuously changed by the deformation effect And it is identified that the hydrodynamic force or torque on any single deforming body includes contributions of linear and angular accelerations of all the bodies, which means that these acceleration constituents should be added to corresponding hydrodynamic loads so as to unsteadily describe motions of the deforming body. In corresponding two dimensional cases, the energy description still holds and may be transformed into the extended unsteady Blasius formulae. Therefore, one can choose any pertinent approach to deal with hydrodynamic interactions among many deformable bodies.

A new lead-free Sn-1.0Ag-0.7Cu-xSnO2 composite solder was smelted in a vacuum arc furnace at 900°C for 30 min. This paper investigated the influence of SnO2 nanoparticles on the microstructure, melting properties and growth of interfacial intermetallic compounds (IMCs) at the interface between Cu and the composite solder during isothermal aging. The results indicated that SnO2 particles effectively refined the β-Sn grains and reduced the size of Cu6Sn5. The thermal analysis data showed that nano-sized SnO2 decreased the pasty range and melting temperature. In addition, the additional nanoparticles reduced the diffusion coefficient and impeded the growth of intermetallic compounds during soldering and aging. The effect of nanoparticles on solder is closely associated with the added amount of nano-SnO2 particles. When the SnO2 concentration was 1.0 wt.%, the composite solder possessed an excellent microstructure, suitable melting properties and obvious inhibition effect on the interfacial IMCs. However, excessive addition of SnO2 particles in the solder alloys decreased the inhibition effect of the interfacial IMCs.

Dielectric breakdown induced by Cu ion migration in porous low-k dielectric films has been investigated in alternating-polarity bias conditions using a metal–insulator–metal capacitor with Cu top metal electrode. The experimental results indicated that Cu ions migrated into the dielectric film under stress with positive polarity, leading to weaker dielectric strength and shorter time to failure (TTF). In the alternating-polarity test, the measured TTFs increased with decreasing stressing frequency, implying backward migration of Cu ions during reverse-bias stress. Additionally, compared with a direct-current stress condition, the measured TTFs were higher as the frequency was decreased to 10−2 Hz. The electric-field acceleration factor for porous low-k dielectric film breakdown in the alternating-polarity test was also found to increase. This Cu backward migration effect is effective when the stressing time under negative polarity is longer than 0.1 s.

Hepatitis C virus (HCV) encodes mechanisms to evade the multilayered antiviral actions of the host immune system. Great progress has been made in elucidating the strategies HCV employs to down-regulate interferon (IFN) production, impede IFN signaling transduction, and impair IFN-stimulated gene (ISG) expression. However, there is a limited understanding of the mechanisms governing how viral proteins counteract the antiviral functions of downstream IFN effectors due to the lack of an efficient approach to identify such interactions systematically. To study the mechanisms by which HCV antagonizes the IFN responses, we have developed a high-throughput profiling platform that enables mapping of HCV sequences critical for anti-IFN function at high resolution. Genome-wide profiling performed with a 15-nt insertion mutant library of HCV showed that mutations in the p7 region conferred high levels of IFN sensitivity, which could be alleviated by the expression of WT p7 protein. This finding suggests that p7 protein of HCV has an immune evasion function. By screening a liver-specific ISG library, we identified that IFI6-16 significantly inhibits the replication of p7 mutant viruses without affecting WT virus replication. In contrast, knockout of IFI6-16 reversed the IFN hypersensitivity of p7 mutant virus. In addition, p7 was found to be coimmunoprecipitated with IFI6-16 and to counteract the function of IFI6-16 by depolarizing the mitochondria potential. Our data suggest that p7 is a critical immune evasion protein that suppresses the antiviral IFN function by counteracting the function of IFI6-16.

Background: Improvements to prognostic models in metastatic castration-resistant prostate cancer have the potential to augment clinical trial design and guide treatment strategies. In partnership with Project Data Sphere, a not-for-profit initiative allowing data from cancer clinical trials to be shared broadly with researchers, we designed an open-data, crowdsourced, DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenge to not only identify a better prognostic model for prediction of survival in patients with metastatic castration-resistant prostate cancer but also engage a community of international data scientists to study this disease. Methods Data from the comparator arms of four phase 3 clinical trials in first-line metastatic castration-resistant prostate cancer were obtained from Project Data Sphere, comprising 476 patients treated with docetaxel and prednisone from the ASCENT2 trial, 526 patients treated with docetaxel, prednisone, and placebo in the MAINSAIL trial, 598 patients treated with docetaxel, prednisone or prednisolone, and placebo in the VENICE trial, and 470 patients treated with docetaxel and placebo in the ENTHUSE 33 trial. Datasets consisting of more than 150 clinical variables were curated centrally, including demographics, laboratory values, medical history, lesion sites, and previous treatments. Data from ASCENT2, MAINSAIL, and VENICE were released publicly to be used as training data to predict the outcome of interestnamely, overall survival. Clinical data were also released for ENTHUSE 33, but data for outcome variables (overall survival and event status) were hidden from the challenge participants so that ENTHUSE 33 could be used for independent validation. Methods were evaluated using the integrated time-dependent area under the curve (iAUC). The reference model, based on eight clinical variables and a penalised Cox proportional-hazards model, was used to compare method performance. Further validation was done using data from a fifth trialENTHUSE M1in which 266 patients with metastatic castration-resistant prostate cancer were treated with placebo alone. Findings 50 independent methods were developed to predict overall survival and were evaluated through the DREAM challenge. The top performer was based on an ensemble of penalised Cox regression models (ePCR), which uniquely identified predictive interaction effects with immune biomarkers and markers of hepatic and renal function. Overall, ePCR outperformed all other methods (iAUC 0·791; Bayes factor >5) and surpassed the reference model (iAUC 0·743; Bayes factor >20). Both the ePCR model and reference models stratified patients in the ENTHUSE 33 trial into high-risk and low-risk groups with significantly different overall survival (ePCR: hazard ratio 3·32, 95% CI 2·394·62, p, European Union within the ERC grant LatentCauses supported the work of C.F and I.K. German Research Foundation (DFG) within the Collaborative Research Centre 1243, subproject A17 awarded to C.F. German Federal Ministry of Education and Research (BMBF) through the Research Consortium e:AtheroMED (Systems medicine of myocardial infarction and stroke) under the auspices of the e:Med Programme (grant # 01ZX1313C) supported the work of D.P.A., P.D., C.F., C.K., I.K., N.K., M.L., H.S. and J.F.S. at the Institute of Computational Biology. NIH Grants RR025747-01, MH086633 and 1UL1TR001111, and NSF Grants SES-1357666, DMS-14-07655 and BCS0826844 supported the work of C.H., J.I., E.L., Y.W., H.Y., H.Z. and J.Z. NSFC Grant Nos. 61332013, 61572139 supported the work of X.L, Y.L, Y.Z., and S.Z. National Natural Science Foundation of China grants [Nos. 61422309, 61379092] was awarded to S.Z. The Patrick C. Walsh Prostate Research Fund and the Johns Hopkins Individualized Health Initiative supported the work of R.Y.C., D.D., Y.D., Z.J., K.R., Z.W. and Y.Z. FCT Ph.D. Grant SFRH/BD/80925/2011 was awarded to S.C. Clinical Persona Inc., East Palo Alto, CA supported the work of L.B. and D.K. The Finnish Cultural Foundation and the Drug Research Doctoral Programme (DRDP) at the University of Turku supported T.D.L. The National Research Foundation Singapore and the Singapore Ministry of Education, under its Research Centres of Excellence initiative, supported the work of J.G. and K.T. A grant from the Russian Science Foundation 14-24-00155 was awarded to M.D.K. A*MIDEX grant (no. ANR-11-IDEX-0001-02) was awarded to P.J.B. NSERC supported the work of R.G. The Israeli Centers of Research Excellence (I-CORE) program (Center No. 4/11) supported the work of E.G. Academy of Finland (grants 292611, 269862, 272437, 279163, 295504), National Cancer Institute (16X064), and Cancer Society of Finland supported the work of T.A. Academy of Finland (grant 268531) supported the work of T.M

A database of refined raw materials and end treatment-based VOCs emission factors for typical solvent use sources was developed for the Pearl River Delta. For this, the impact of composition and the content of raw materials, production process, and comprehensive end treatment on the emission of VOCs was analyzed. The solvent use sources included printing, furniture manufacturing, and electronic component and equipment manufacturing. The results showed that the main VOCs in the raw materials used in printing were ethyl acetate, propyl acetate, isopropanol, propanol, and ethanol, which contributed 60%-80% to the total amount of VOCs. Ethyl acetate and butyl acetate were the main oxygenated VOCs (OVOCs) from the raw materials used in furniture manufacturing, contributing 45%-65% of the total. The main VOCs from the raw materials used in electronic component and equipment manufacturing were OVOCs such as alcohols, ethers and phenols, BTEX, and halohydrocarbons. The uncontrolled and controlled emission factors for VOCs from printing were 415.2 kg·t

Drug-resistant mutations often have deleterious impacts on replication fitness, posing a fitness cost that can only be overcome by compensatory mutations. However, the role of fitness cost in the evolution of drug resistance has often been overlooked in clinical studies or in vitro selection experiments, as these observations only capture the outcome of drug selection. In this study, we systematically profile the fitness landscape of resistance-associated sites in HIV-1 protease using deep mutational scanning. We construct a mutant library covering combinations of mutations at 11 sites in HIV-1 protease, all of which are associated with resistance to protease inhibitors in clinic. Using deep sequencing, we quantify the fitness of thousands of HIV-1 protease mutants after multiple cycles of replication in human T cells. Although the majority of resistance-associated mutations have deleterious effects on viral replication, we find that epistasis among resistance-associated mutations is predominantly positive. Furthermore, our fitness data are consistent with genetic interactions inferred directly from HIV sequence data of patients. Fitness valleys formed by strong positive epistasis reduce the likelihood of reversal of drug resistance mutations. Overall, our results support the view that strong compensatory effects are involved in the emergence of clinically observed resistance mutations and provide insights to understanding fitness barriers in the evolution and reversion of drug resistance., Author summary Antiretroviral drugs have achieved great success in controlling the HIV pandemic. However, the therapy fails sometimes owing to the low drug adherence and/or the emergence of resistance associated mutations on viral genome. The persistence of drug resistance poses challenges in using antiretroviral drugs for long term control or pre-exposure prophylaxis. To understand the mechanisms of resistance evolution and persistence, we profiled the replication fitness of over 1000 HIV-1 mutants with combinations of resistance associated mutations on its protease gene. We found that although resistance associated mutations greatly reduce replication fitness, they interact positively to alleviate the mutational load. These genetic interactions, termed epistasis, increase the ruggedness along the evolution paths, restricting resistance associated mutations from reversal. Our data support the clinical observations that drug resistance mutations tend to persist even when antiretroviral drug is discontinued.

Ratoon stunting disease (RSD), one of the most important diseases of sugarcane, is caused by the bacterium

Summary Assembly of Kaposi’s sarcoma-associated herpesvirus (KSHV) begins at a bacteriophage-like portal complex that nucleates formation of an icosahedral capsid with capsid-associated tegument complexes (CATCs) and facilitates translocation of an ∼150-kb dsDNA genome, followed by acquisition of a pleomorphic tegument and envelope. Because of deviation from icosahedral symmetry, KSHV portal and tegument structures have largely been obscured in previous studies. Using symmetry-relaxed cryo-EM, we determined the in situ structure of the KSHV portal and its interactions with surrounding capsid proteins, CATCs, and the terminal end of KSHV’s dsDNA genome. Our atomic models of the portal and capsid/CATC, together with visualization of CATCs’ variable occupancy and alternate orientation of CATC-interacting vertex triplexes, suggest a mechanism whereby the portal orchestrates procapsid formation and asymmetric long-range determination of CATC attachment during DNA packaging prior to pleomorphic tegumentation/envelopment. Structure-based mutageneses confirm that a triplex deep binding groove for CATCs is a hotspot that holds promise for antiviral development., Graphical Abstract, Highlights • Genome-packing portal and capsid-associated tegument complexes (CATCs) resolved • Partial and asymmetric CATC occupancy introduces structural variability • CATC binding introduces 120° counterclockwise rotation of triplex Ta on the capsid • Structure-based mutageneses reveal binding hotspot for antiviral development, Resolution of KSHV’s asymmetric icosahedral structure is achieved via symmetry-relaxed cryo-EM using sequential localized classification. Interactions between the DNA-translocating portal protein, associated capsid and tegument proteins, and the viral genome reveal surprising variability in tegument protein occupancy and orientation plasticity.

Renal fibrosis has been regarded as the common pathway of end-stage renal failure. Understanding the fundamental mechanism that leads to renal fibrosis is essential for developing better therapeutic options for chronic kidney diseases. So far, the main abstractions are on the injury of tubular epithelial cells, activation of interstitial cells, expression of chemotactic factor and adhesion molecule, infiltration of inflammatory cells and homeostasis of ECM. However, emerging studies revealed that endothelial cells (ECs) might happen to endothelial-to-mesenchymal transition (EndMT) dependent and/or independent endothelial dysfunction, which were supposed to accelerate renal fibrosis and are identified as new mechanisms for the proliferation of myofibroblasts as well. In this chapter, we are about to interpret the role of ECs in renal fibrosis and analyze the related molecules and pathways of both EndMT and EndMT independent endothelial dysfunction.

Background Recent advancements in next-generation sequencing have rapidly improved our ability to study genomic material at an unprecedented scale. Despite substantial improvements in sequencing technologies, errors present in the data still risk confounding downstream analysis and limiting the applicability of sequencing technologies in clinical tools. Computational error correction promises to eliminate sequencing errors, but the relative accuracy of error correction algorithms remains unknown. Results In this paper, we evaluate the ability of error correction algorithms to fix errors across different types of datasets that contain various levels of heterogeneity. We highlight the advantages and limitations of computational error correction techniques across different domains of biology, including immunogenomics and virology. To demonstrate the efficacy of our technique, we apply the UMI-based high-fidelity sequencing protocol to eliminate sequencing errors from both simulated data and the raw reads. We then perform a realistic evaluation of error-correction methods. Conclusions In terms of accuracy, we find that method performance varies substantially across different types of datasets with no single method performing best on all types of examined data. Finally, we also identify the techniques that offer a good balance between precision and sensitivity.

Elizabethkingia genus is emerging in hospitals and resistant to multiple antibiotics. The intrinsic imipenem resistance of Elizabethkingia genus is related to two chromosome-encoded metallo-beta-lactamases (MBLs), BlaB and GOB. This study was aimed to investigate the in vitro activity of imipenem, vancomycin, and rifampicin in clinical Elizabethkingia species. The distribution and heterogeneity of MBLs responsible for imipenem resistance were also evaluated. A total of 167 Elizabethkingia isolates from different patients were collected, including E. anophelis (142), E. meningoseptica (11), and E. miricola (14). All isolates were evaluated by the broth microdilution assay, ethylenediaminetetraacetic acid (EDTA) combination disk test, and EDTA-based microdilution test. The characteristics of BlaB and GOB were evaluated in phylogenetic analysis and heterologous expression experiments. Most of the isolates were susceptible to rifampin (94%), whereas none of the isolates were susceptible to imipenem. Vancomycin showed intermediate effectiveness. EDTA could reduce 4 folds or more minimum inhibitory concentrations (MICs) of imipenem in 105 isolates (62.9%). Of the isolates, the amino acid sequences of BlaB and GOB were divided into 22 and 25 different types, respectively. Phylogenetic analysis showed BlaB and GOB are species-specific proteins. Furthermore, GOB and BlaB from E. anophelis showed higher imipenem hydrolysis efficiency than those from the other two species. Rifampicin remained the most active agent in the current study. The mechanism of Elizabethkingia resistance to imipenem primarily stemmed from MBLs but other mechanisms could also exist, which requires further investigation.