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Abstract: Intrauterine infection of fetuses with West Nile virus (WNV) has been implicated in cases of women infected during pregnancy. Infection of timed-pregnant mice on 5.5, 7.5, and 9.5 days post-coitus (dpc) resulted in fetal infection. Infection of dams on 11.5 and 14.5 dpc resulted in little and no fetal infection, respectively. Pre-implantation embryos in culture were also infected with WNV after the blastocyst stage and the formation of trophectoderm. Green fluorescent protein (GFP) expression was observed in a trophoblast stem (TS) cell line after infection with a GFP-expressing WNV construct. However, no fluorescence was observed in differentiated trophoblast giant cell (TGC) cultures. GFP fluorescence was present in TGC cultures if infected TS cells were induced to differentiate. These results suggest that embryos are susceptible to WNV infection after the formation of the trophectoderm around 3.5 dpc through the formation of the functional placenta around 10.5 dpc. [Copyright &y& Elsevier]

Abstract: Rock fragments are a common occurrence in many arid and semiarid areas and can act as an effective dust trap. In the previous studies, dust accumulation on rock fragment substrata was investigated in a single stone layer, with stones of an identical size. The objective of the present study was to explore the effect of the number and the textural composition of pebble layers on aeolian dust accumulation in the semiarid loess area of NW China. The results of the experiment indicate that pebble layers have obvious effect upon dust accumulation. The effect was very pronounced for two layers of pebbles as compared to one layer. Dust accumulation on pebbles increased with increasing number of pebble layers. Total dust accumulation and accumulation between and underneath the pebbles in a single layer was significantly less than in two and three layers, however, no significant difference in dust accumulation was found between two and three layers. This suggests that a double layer of pebbles may be a better aeolian trap than single, triple or multi-layered pebble surfaces. The textural composition of a pebble surface has only minor effects on dust accumulation. Dust quantity on the pebbles was almost identical for all the combinations tested. Total dust accumulation and accumulation between and underneath the pebbles tended to increase with increasing proportion of small-size pebbles. The results of the study might be of use for proper management of gravel-mulched fields and stone barriers used for wind erosion control in the arid regions. [Copyright &y& Elsevier]

Background Obesity is an increasing health problem in developed countries, where the prevalence of Helicobacter pylori infection is decreasing. Recent studies suggested colonization of the stomach by H pylori might affect gastric expression of appetite- and satiety-related hormone and patients cured of H pylori infection gained weight. It was hypothesized that H pylori could be a contributing pathogenic factor in childhood and adult obesity. Methods To determine whether H pylori infection is linked to obesity, a case-control study composed of 414 patients with morbid obesity (a body mass index [calculated as weight in kilograms divided by the square of height in meters] of ≥35 with serious comorbidity or a body mass index of ≥40) and 683 control subjects (a body mass index of <25) with a comparable socioeconomic status was conducted. Immunoglobulin G antibodies against H pylori were measured from frozen serum samples by an enzyme-linked immunosorbent assay. Logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI). Results The overall seropositivity was significantly lower in obese patients (181 [43.7%] of 414) than controls (410 [60.0%] of 683) (OR, 0.50; 95% CI, 0.39-0.65; P<.001). Differences in the estimated risk of the presence of H pylori were more pronounced in younger age groups, with ORs of 0.32 (95% CI, 0.10-1.00; P = .05) in those aged 10 to 19 years, 0.55 (95% CI, 0.34-0.89; P = .01) in those aged 20 to 29 years, 0.49 (95% CI, 0.30-0.80; P = .007) in those aged 30 to 39 years, and 0.58 (95% CI, 0.33-1.00; P = .05) in those aged 40 years or older. Conclusions Our data indicated an inverse relationship between morbid obesity and H pylori seropositivity. These findings raise the hypothesis that a lack of H pylori infection, especially during childhood, might enhance the risk of the development of morbid obesity. [ABSTRACT FROM AUTHOR]

West Nile (WN) virus was found throughout New York State in 2000, with the epicenter in New York City and surrounding counties. We tested 3,403 dead birds and 9,954 mosquito pools for WN virus during the transmission season. Sixty-three avian species, representing 30 families and 14 orders, tested positive for WN virus. The highest proportion of dead birds that tested positive for WN virus was in American Crows in the epicenter (67% positive, n = 907). Eight mosquito species, representing four genera, were positive for WN virus. The minimum infection rate per 1,000 mosquitoes (MIR) was highest for Culex pipiens in the epicenter: 3.53 for the entire season and 7.49 for the peak week of August 13. Staten Island had the highest MIR (11.42 for Cx. pipiens), which was associated with the highest proportion of dead American Crows that tested positive for WN virus (92%, n = 48) and the highest number of human cases (n = 10). [ABSTRACT FROM AUTHOR]

We analyzed nucleotide sequences from the envelope gene of 11 West Nile (WN) virus strains collected in New York State during the 2000 transmission season to determine whether they differed genetically from each other and from the initial strain isolated in 1999. The complete envelope genes of these strains were amplified by reverse transcription-polymerase chain reaction. The resulting sequences were aligned, the genetic distances were computed, and a phylogenetic tree was constructed. Ten (0.7%) of 1,503 positions in the envelope gene were polymorphic in one or more sequences. The genetic distances were 0.003 or less. WN virus strains circulating in 2000 were homogeneous with respect to one another and to a strain isolated in 1999. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Advances in the development of new tuberculosis drugs and treatment regimens," by A. Zumla and colleagues in the 2013 issue.

Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing activity. Two mAbs (COV2-2676 and COV2-2489) inhibited infection of authentic SARS-CoV-2 and recombinant VSV/SARS-CoV-2 viruses. We mapped their binding epitopes by alanine-scanning mutagenesis and selection of functional SARS-CoV-2 S neutralization escape variants. Mechanistic studies showed that these antibodies neutralize in part by inhibiting a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 offered protection either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, natural infection induces a subset of potent NTD-specific mAbs that leverage neutralizing and Fc-mediated activities to protect against SARS-CoV-2 infection using multiple functional attributes. [Display omitted] • Natural SARS-2 infection induces a subset of potent N-terminal domain-specific mAbs • N-terminal domain reactive human monoclonal antibodies can neutralize live virus • COV2-2676 and COV2-2489 offer protection in a hACE2-transgenic mouse model • COV2-2676 and COV2-2489 Fc-effector functions are essential for optimal protection Suryadevara et al. find human neutralizing antibodies to the spike protein N-terminal domain that arise from natural infection with SARS-CoV-2. These antibodies inhibit post-attachment steps of the viral cycle and initiate protective immune responses via the antibody Fc domain. [ABSTRACT FROM AUTHOR]

The biosafety level 3 (BSL-3) requirement to culture severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a bottleneck for research. Here, we report a trans -complementation system that produces single-round infectious SARS-CoV-2 that recapitulates authentic viral replication. We demonstrate that the single-round infectious SARS-CoV-2 can be used at BSL-2 laboratories for high-throughput neutralization and antiviral testing. The trans -complementation system consists of two components: a genomic viral RNA containing ORF3 and envelope gene deletions, as well as mutated transcriptional regulator sequences, and a producer cell line expressing the two deleted genes. Trans- complementation of the two components generates virions that can infect naive cells for only one round but does not produce wild-type SARS-CoV-2. Hamsters and K18-hACE2 transgenic mice inoculated with the complementation-derived virions exhibited no detectable disease, even after intracranial inoculation with the highest possible dose. Thus, the trans -complementation platform can be safely used at BSL-2 laboratories for research and countermeasure development. [Display omitted] • A trans -complementation system produces single-round infectious SARS-CoV-2 • Single-round infectious SARS-CoV-2 recapitulates authentic viral infection • Safety results support the trans -complementation system can be performed at BSL-2 • Trans -complementation assay can be used for high-throughput antiviral tests at BSL-2 Zhang et al. develop a trans- complementation system to produce single-round infectious SARS-CoV-2 that recapitulates authentic viral infection and replication. They then show the system can be safely used at biosafety level 2 for high-throughput antiviral testing. [ABSTRACT FROM AUTHOR]

Reference 1 Xu P, Shan C, Dunn TJ, Xie X, Xia H, Gao J, et al. (2020) Role of microglia in the dissemination of Zika virus from mother to fetal brain. The fourteenth author's name is spelled incorrectly. [Extracted from the article]

The retrieval-extinction paradigm, a non-invasive memory intervention that is methodologically similar to exposure therapy, has significant clinical application prospects for targeting memory reconsolidation. However, it is difficult to distinguish whether the effect of preventing the return of fear by retrieval-extinction depends upon the reconsolidation-based mechanism or extinction-based mechanism. This study tested extinction retention shortly after intervention to determine whether retrieval-extinction is a reconsolidation-based approach or extinction-based approach as well as exploring the effect of sleep. In our experiment, the effects on fear conditional memory of standard extinction, retrieval-extinction, and extinction-retrieval were compared using the fear test at 3 h, 12 h without a night's sleep, and 12 h with a night's sleep after the intervention. The results showed that standard extinction and extinction-retrieval procedures reduce fear 3 h after intervention, while retrieval-extinction procedure reduces fear 12 h with a night's sleep after the intervention. The results suggest that standard extinction and extinction-retrieval create an extinction memory trace that competes with original memory trace, only retrieval-extinction update the original memory trace through memory reconsolidation. These findings provide solid evidence for the reconsolidation mechanism of the retrieval-extinction paradigm and highlight the effect of sleep on memory reconsolidation. • Both retrieval-extinction and extinction-retrieval procedures can prevent fear relapse. • Fear reduction effect of standard extinction and extinction-retrieval are apparent immediately after intervention. • Fear reduction effect of retrieval-extinction is not apparent immediately after intervention. • One night of sleep is necessary to observe the retrieval-extinction effect of fear reduction. [ABSTRACT FROM AUTHOR]

Background: This study aimed to quantify the dosimetric differences between the planned and delivered dose to tumor and normal organs in locally advanced non-small cell lung cancer (LANSCLC) treated with hypofractionated radiotherapy (HRT), and to explore the necessity and identify optimal candidates for adaptive radiotherapy (ART).Methods: Twenty-seven patients with stage III NSCLC were enrolled. Planned radiation dose was 51Gy in 17 fractions with cone-beam CT (CBCT) acquired at each fraction. Virtual CT was generated by deformable image registration (DIR) of the planning CT to CBCT for dose calculation and accumulation. Dosimetric parameters were compared between original and accumulated plans using Wilcoxon signed rank test. Correlations between dosimetric differences and clinical variables were analyzed using Mann-Whitney U test or Chi-square test.Results: Patients had varied gross tumor volume (GTV) reduction by HRT (median reduction rate 11.1%, range - 2.9-44.0%). The V51 of planning target volume for GTV (PTV-GTV) was similar between original and accumulated plans (mean, 88.2% vs. 87.6%, p = 0.452). Only 11.1% of patients had above 5% relative decrease in V51 of PTV-GTV in accumulated plans. Compared to the original plan, limited increase (median relative increase < 5%) was observed in doses of total lung (mean dose, V20 and V30), esophagus (mean dose, maximum dose) and heart (mean dose, V30 and V40) in accumulated plans. Less than 30% of patients had above 5% relative increase of lung or heart doses. Patients with quick tumor regression or baseline obstructive pneumonitis showed more notable increase in doses to normal structures. Patients with baseline obstructive atelectasis showed notable decrease (10.3%) in dose coverage of PTV-GTV.Conclusions: LANSCLC patients treated with HRT had sufficient tumor dose coverage and acceptable normal tissue dose deviation. ART should be applied in patients with quick tumor regression and baseline obstructive pneumonitis/atelectasis to spare more normal structures. [ABSTRACT FROM AUTHOR]

Based on genome-scale loss-of-function screens we discovered that Topoisomerase III-β (TOP3B), a human topoisomerase that acts on DNA and RNA, is required for yellow fever virus and dengue virus-2 replication. Remarkably, we found that TOP3B is required for efficient replication of all positive-sense-single stranded RNA viruses tested, including SARS-CoV-2. While there are no drugs that specifically inhibit this topoisomerase, we posit that TOP3B is an attractive anti-viral target. • Topoisomerase III-ß (TOP3B) is a host factor for all single stranded positive strand RNA viruses. • TOP3B is not a host factor for Ebola and influenza viruses, which are negative strand RNA viruses. • TOP3B acts directly on the viral genome of DENV2. • TOP3B could be a target for antiviral development. [ABSTRACT FROM AUTHOR]

The effective treatment for dengue virus infection continues to be a challenge. We herein reported our continued SAR exploration on the spiropyrazolopyridone scaffold. Introducing different substituents at the 3́- or 5́-site of the pyrazolopyridone core or moving the benzyl chain to the adjacent nitrogen led to a significant loss of potency on DENV-2. While a narrow range of substitutions were tolerated at the para -position of the phenyl ring, di-substitution on the phenyl ring is beneficial for DENV-2 potency and has variable influences on DENV-3 potency depending on the exact compound. Among these molecules, compounds 22 (JMX0376) with 4-chloro-3-fluorobenzyl and 24 (JMX0395) with 2,4-bis(trifluoromethyl)benzyl showed the most potent and broadest inhibitory activities against DENV-1 to −3 with nanomolar to low micromolar EC 50 values. [ABSTRACT FROM AUTHOR]

Seasonal changes in CO 2 exchange determine the strength and dynamics of the carbon budget in terrestrial ecosystems. Knowledge about seasonal and spatial variations in carbon fluxes (net ecosystem productivity (NEP), gross primary productivity (GPP), and ecosystem respiration (RE)) is thus essential to support accurate modeling of carbon flux dynamics. To the best of our knowledge, this study represents the first comprehensive evaluation of how carbon fluxes vary seasonally in different ecoregions in China. Using eddy covariance measurements from ChinaFLUX, we analyzed the spatial variations and climate controls of the phenological and physiological properties of NEP, GPP, and RE across China. Apart from the beginning and ending day of NEP (net carbon uptake), the phenological properties of the carbon fluxes varied significantly with latitude; however, there were no evident trends in the physiological properties of the carbon fluxes with latitude (apart from the annual values of GPP and RE, known as AGPP and ARE). The spatial variation in the physiological properties of GPP and RE was influenced by the precipitation patterns, while the spatial distribution of the phenological properties of GPP and RE was related to air temperature. Moreover, the spatial variation for the end of the growing season changed with the autumn mean soil temperatures. The factors that contributed to the spatial distribution in the annual NEP (ANEP) and annual GPP and RE (AGPP and ARE) were quite different. The mean daily GPP and RE were the main contributors to the spatial variations in AGPP and ARE, while the net carbon uptake period was the main contributor to the spatial variation in ANEP. In this study, we identified a series of ecological parameters and reference values for seasonal patterns that can be used to validate models that simulate changes in regional carbon fluxes. [ABSTRACT FROM AUTHOR]

• Different patterns between plant nitrogen (N) and phosphorus (P) in community were detected in alpine grasslands. • The coupling between plant N and P were mediated by the water and heat availability. • Plants tend to be more flexible in their N:P stoichiometry at high variability of soil nutrient in arid environments. • Plant N and P tightly coupled at higher soil nutrient availability and less nutrient variability. The biogeochemical cycles of plant nitrogen (N) and phosphorus (P) are interlinked by ecological processes, and the N and P cycles become uncoupled in response to global change experiments. However, the complex natural hydrothermal conditions in arid, semiarid and humid grassland ecosystems may have different effects on the availability of soil nutrients and moisture and may induce different balances between the N and P cycles. Here, we evaluated how the aridity index (AI) affects the balance between N and P of alpine grassland by the collected 115 sites along water and heat availability gradients on the Tibetan Plateau. We found that AI was negatively related to the variation in the coefficients of soil total dissolved N (TDN) and soil availability of P (SAP), and positive effects of AI, TDN and SAP on the coupling of plant N and P were detected. Thus, AI was positively correlated with soil nutrients and moisture, which may favor the co-uptake of soil nutrients by plants, resulting in a small variation in plant N and P in humid environments. Conversely, in arid environments with temporally variable soil nutrients, the plants tend to be more flexible in their N:P stoichiometry. Generally, our findings suggest that plant N and P could be more strongly coupled in humid conditions than in arid environments across alpine grasslands, with potential decoupling of the N biogeochemical cycle from P in an arid environment with an asynchronous dynamic of temperature and precipitation. [ABSTRACT FROM AUTHOR]

Bacterial endosymbionts such as Rickettsia and Wolbachia play prominent roles in the development and behaviour of their insect hosts, such as whiteflies, aphids, psyllids and mealybugs. Accumulating studies have emphasized the importance of establishing experimental insect populations that are either lacking or bearing certain species of endosymbionts, because they are the basis in which to reveal the biological role of individual symbionts. In this study, using Rickettsia as an example, we explored a "single-pair screening" method to establish Rickettsia infected and uninfected populations of whitefly Bemisia tabaci MEAM1 for further experimental use. The original host population had a relatively low infection rate of Rickettsia (< 35%). When B. tabaci adults newly emerged, unmated males and females were randomly selected, and released into a leaf cage that covered a healthy plant leaf in order to oviposit F1 generation eggs. Following 6 days of oviposition, the parents were recaptured and used for PCR detection. The F1 progeny, for which parents were either Rickettsia positive or negative, were used to produce the F2 generation, and similarly in turn for the F3, F4 and F5 generations respectively; if the infection status of Rickettsia was consistent in the F1 to F5 generations, then the populations can be used as Rickettsia positive or negative lines for further experiments. In addition, our phylogenetic analyses revealed that Rickettsia has high fidelity during the maternal transmission in different generations. • Symbiotic bacteria play prominent roles in the development of their insect hosts. • Availability of infected and uninfected hosts are the basis to reveal symbiont roles. • Single-pair screening method was introduced to set up different symbiotic hosts. • Whiteflies and endosymbiont Rickettsia were used as examples in this study. • Rickettsia has high fidelity during the maternal transmission between generations. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) has drawn global attention as the etiologic agent of Zika Congenital Syndrome in babies born to infected pregnant women. To prevent future ZIKV outbreaks and protect persons at risk for severe disease, we developed two live-attenuated vaccine (LAV) candidates containing 10- or 20-nucleotide deletions in the 3′UTR of the viral genome (Δ10 and Δ20). After a single-dose immunization, both Δ10 and Δ20 LAVs protected mice and non-human primates against ZIKV infection. Here, we characterized the stability, safety, and efficacy of the LAVs after continuously culturing them on manufacture Vero cells for ten rounds. Whole genome sequencing showed that passage 10 (P10) LAVs retained the engineered Δ10 and Δ20 deletions; one to four additional mutations emerged at different regions of the genome. In A129 mice, the P10 LAVs exhibited viremia higher than the un-passaged LAVs, but lower than wild-type ZIKV; unlike wild-type ZIKV-infected mice, none of the P10 LAV-infected mice developed disease or death, demonstrating that the P10 LAVs remained attenuated. Mice immunized with a single dose of the P10 LAVs developed robust neutralizing antibody titers (1/1,000 to 1/10,000) and were protected against epidemic ZIKV challenge. The P10 LAVs did not exhibit increased neurovirulence. Intracranial inoculation of one-day-old CD1 pups with 103 focus-forming units of the P10 Δ10 and Δ20 LAVs resulted in 100% and ≥80% survival, respectively. Furthermore, the P10 LAVs remained incompetent in infecting Aedes aegypti mosquitoes after intrathoracic microinjection. Our results support the phenotypic stability and further development of these promising LAVs for ZIKV. • The 3′UTR live-attenuated Zika vaccines were stable in retaining the engineered deletions after culturing on Vero cells. • Additional changes occurred in the viral genome after continuously culturing the live-attenuated vaccines on Vero cells. • The passage 10 vaccines retained safety, immunogenicity, and efficacy, and do not increase neurovirulence. • The 3′UTR live-attenuated Zika vaccines cannot infect Aedes aegypti mosquitoes. • The demonstrated genetic and phenotypic stabilities warrant further development of the 3′UTR live-attenuated Zika vaccines. [ABSTRACT FROM AUTHOR]

Summary Although interferon-induced proteins with tetratricopeptide repeats (IFIT proteins) inhibit infection of many viruses by recognizing their RNA, the regulatory mechanisms involved remain unclear. Here we report a crystal structure of cap 0 (m 7 GpppN) RNA bound to human IFIT1 in complex with the C-terminal domain of human IFIT3. Structural, biochemical, and genetic studies suggest that IFIT3 binding to IFIT1 has dual regulatory functions: (1) extending the half-life of IFIT1 and thereby increasing its steady-state amounts in cells; and (2) allosterically regulating the IFIT1 RNA-binding channel, thereby enhancing the specificity of recognition for cap 0 but not cap 1 (m 7 GpppNm) or 5′-ppp RNA. Mouse Ifit3 lacks this key C-terminal domain and does not bind mouse Ifit1. The IFIT3 interaction with IFIT1 is important for restricting infection of viruses lacking 2′-O methylation in their RNA cap structures. Our experiments establish differences in the regulation of IFIT1 orthologs and define targets for modulation of human IFIT protein activity. [ABSTRACT FROM AUTHOR]