The respiratory virus responsible for coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected nearly every aspect of life worldwide, claiming ...the lives of over 3.9 million people globally, at the time of this publication. Neutralizing humanized nanobody (V
H)-based antibodies (V
H-huFc) represent a promising therapeutic intervention strategy to address the current SARS-CoV-2 pandemic and provide a powerful toolkit to address future virus outbreaks. Using a synthetic, high-diversity V
H bacteriophage library, several potent neutralizing V
H-huFc antibodies were identified and evaluated for their capacity to tightly bind to the SARS-CoV-2 receptor-binding domain, to prevent binding of SARS-CoV-2 spike (S) to the cellular receptor angiotensin-converting enzyme 2, and to neutralize viral infection. Preliminary preclinical evaluation of multiple V
H-huFc antibody candidates demonstrate that they are prophylactically and therapeutically effective
against
SARS-CoV-2. The identified and characterized V
H-huFc antibodies described herein represent viable candidates for further preclinical evaluation and another tool to add to our therapeutic arsenal to address the COVID-19 pandemic.
The systematic construction of heterogeneous nanoparticles composed of two distinct metal domains (Au and Pt) and exhibiting a broad range of morphologically defined shapes is reported. It is ...demonstrated that careful Au overgrowth on Pt nanocrystal seeds with shapes mainly corresponding to cubeoctahedra, octahedra and octapods can lead to heterometallic systems whose intrinsic structures result from specific epitaxial relationships such as {111} + {111}, {200} + {200} and {220} + {220}. Comprehensive analysis shows also that nanoparticles grown from octahedral seeds can be seen as comprising of four Au tetrahedral subunits and one Pt octahedral unit in a cyclic arrangement that is similar to the corresponding one in decahedral gold nanoparticles. However, in the present case, the multi-component system is characterized by a broken five-fold rotational symmetry about the 011 axis. This set of bimetallic dimers could provide new platforms for fuel cell catalysts and plasmonic devices.
Circular single-stranded DNA (ssDNA) viruses are the smallest viruses known to infect eukaryotes. High recombination and mutation rates have conferred these viruses with an evolutionary potential ...that has facilitated their emergence. Their damaging effects on livestock (circoviruses) and crops (geminiviruses and nanoviruses), and the ubiquity of anelloviruses in human populations and other mammalian species, have resulted in increased interest in better understanding their epidemiology and infection mechanisms. Circular ssDNA viral replication involves the synthesis of dsDNA intermediates containing complementary-sense (CS) and virion-sense (VS) strands. Precise quantification of VS and CS accumulation during viral infections can provide insights into the molecular mechanisms underlying viral replication and the host invasion process. Although qPCR protocols for quantifying viral molecules exist, none of them discriminate VS and CS strands. Here, using a two-step qPCR protocol we have quantified VS and CS molecule accumulation during the infection process of Tomato yellow leaf curl virus (TYLCV) and Tomato yellow leaf curl Sardinia virus (TYLCSV) (genus Begomovirus, family Geminiviridae). Our results show that the VS/CS strand ratio and overall dsDNA amounts vary throughout the infection process. Moreover, we show that these values depend on the virus-host combination, and that most CS strands are present as double-stranded molecules.
Cellular entry of paramyxoviruses requires the coordinated action of both the attachment (G/H/HN) and fusion (F) glycoproteins, but how receptor binding activates G to trigger F-mediated fusion ...during viral entry is not known. Here, we identify a receptor (ephrinB2)-induced allosteric activation site in Nipah virus (NiV) G involved in triggering F-mediated fusion. We first generated a conformational monoclonal antibody (monoclonal antibody 45 (Mab45)) whose binding to NiV-G was enhanced upon NiV-G-ephrinB2 binding. However, Mab45 also inhibited viral entry, and its receptor binding-enhanced (RBE) epitope was temperature-dependent, suggesting that the Mab45 RBE epitope on G may be involved in triggering F. The Mab45 RBE epitope was mapped to the base of the globular domain (β6S4/β1H1). Alanine scan mutants within this region that did not exhibit this RBE epitope were also non-fusogenic despite their ability to bind ephrinB2, oligomerize, and associate with F at wild-type (WT) levels. Although circular dichroism revealed conformational changes in the soluble ectodomain of WT NiV-G upon ephrinB2 addition, no such changes were detected with soluble RBE epitope mutants or short-stalk G mutants. Additionally, WT G, but not a RBE epitope mutant, could dissociate from F upon ephrinB2 engagement. Finally, using a biotinylated HR2 peptide to detect pre-hairpin intermediate formation, a cardinal feature of F-triggering, we showed that ephrinB2 binding to WT G, but not the RBE-epitope mutants, could trigger F. In sum, we implicate the coordinated interaction between the base of NiV-G globular head domain and the stalk domain in mediating receptor-induced F triggering during viral entry.
Huanglongbing (HLB) is one of the most destructive diseases threatening citriculture worldwide. This disease has been associated with α-proteobacteria species, namely
Liberibacter. Due to the ...unculturable nature of the causal agent, it has been difficult to mitigate the disease, and nowadays a cure is not available. MicroRNAs (miRNAs) are key regulators of gene expression, playing an essential role in abiotic and biotic stress in plants including antibacterial responses. However, knowledge derived from non-model systems including
Liberibacter asiaticus (
Las)-citrus pathosystem remains largely unknown. In this study, small RNA profiles from Mexican lime (
) plants infected with
Las at asymptomatic and symptomatic stages were generated by sRNA-Seq, and miRNAs were obtained with ShortStack software. A total of 46 miRNAs, including 29 known miRNAs and 17 novel miRNAs, were identified in Mexican lime. Among them, six miRNAs were deregulated in the asymptomatic stage, highlighting the up regulation of two new miRNAs. Meanwhile, eight miRNAs were differentially expressed in the symptomatic stage of the disease. The target genes of miRNAs were related to protein modification, transcription factors, and enzyme-coding genes. Our results provide new insights into miRNA-mediated regulation in
in response to
Las infection. This information will be useful to understand molecular mechanisms behind the defense and pathogenesis of HLB.
Abstract
Ton 34 recently transitioned from non-absorbing quasar into a broad absorption line quasi-stellar object. Here, we report new HST-STIS observations of this quasar. Along with C iv ...absorption, we also detect absorption by NV+Lyα and possibly O vi+Lyβ. We follow the evolution of the C iv BAL, and find that, for the slower outflowing material, the absorption trough varies little (if at all) on a rest-frame time-scale of ∼2 yr. However, we detect a strong deepening of the absorption in the gas moving at larger velocities (−20 000 to −23 000 km s−1). The data is consistent with a multistreaming flow crossing our line of sight to the source. The transverse velocity of the flow should be ∼ few thousand km s−1, similar to the rotation velocity of the BLR gas (≈2 600 km s−1). By simply assuming Keplerian motion, these two components must have similar locations, pointing to a common outflow forming the BLR and the BAL. We speculate that BALs, mini-BALs and NALs are part of a common, ubiquitous, accretion-disc outflow in AGN, but become observable depending on the viewing angle towards the flow. The absorption troughs suggest a wind covering only ∼20 per cent of the emitting source, implying a maximum size of 10−3 pc for the clouds forming the BAL/BLR medium. This is consistent with constraints of the BLR clouds from X-ray occultations. Finally, we suggest that the low excitation broad emission lines detected in the spectra of this source lie beyond the wind, and this gas is probably excited by the shock of the BAL wind with the surrounding medium.
In this paper, we revisit the q-state clock model for small systems. We present results for the thermodynamics of the q-state clock model for values from q = 2 to q = 20 for small square lattices of ...L × L , with L ranging from L = 3 to L = 64 with free-boundary conditions. Energy, specific heat, entropy, and magnetization were measured. We found that the Berezinskii–Kosterlitz–Thouless (BKT)-like transition appears for q > 5, regardless of lattice size, while this transition at q = 5 is lost for L < 10; for q ≤ 4, the BKT transition is never present. We present the phase diagram in terms of q that shows the transition from the ferromagnetic (FM) to the paramagnetic (PM) phases at the critical temperature T 1 for small systems, and the transition changes such that it is from the FM to the BKT phase for larger systems, while a second phase transition between the BKT and the PM phases occurs at T 2. We also show that the magnetic phases are well characterized by the two-dimensional (2D) distribution of the magnetization values. We made use of this opportunity to carry out an information theory analysis of the time series obtained from Monte Carlo simulations. In particular, we calculated the phenomenological mutability and diversity functions. Diversity characterizes the phase transitions, but the phases are less detectable as q increases. Free boundary conditions were used to better mimic the reality of small systems (far from any thermodynamic limit). The role of size is discussed.
Background Best practices to improve diversity, equity, and inclusion (DEI) in the biomedical workforce remain poorly understood. The Accreditation Council for Graduate Medical Education launched the ...Barbara Ross-Lee, DO, Diversity, Equity, and Inclusion award for sponsoring institutions to celebrate efforts to improve DEI in graduate medical education (GME).
Objective To identify themes in practices used by award applicants to improve DEI efforts at their institutions, using a qualitative design.
Methods This qualitative study employed an exploratory, inductive approach and constant comparative method to analyze award applications from 2 submission cycles (2020, 2021). Data analysis involved the use of a preliminary codebook of 29 program applications used in a previous study, which was modified and expanded, to perform a subsequent analysis of 12 sponsoring institution applications. Seven adjudication sessions were conducted to ensure coding consistency and resolve disagreements, resulting in the identification of final themes.
Results Institutions’ approaches to advancing DEI resulted from work within 5 themes and 10 subthemes. The themes encompassed organizational commitment (policies that reflect DEI mission), data infrastructure (tracking recruitment, retention, and inclusion efforts), community connection (service-learning opportunities), diverse team engagement (coproduction with residents), and systematic strategies for DEI support throughout the educational continuum. Consistent across themes was the importance of collaboration, avoiding silos, and the need for a comprehensive longitudinal approach to DEI to achieve a diverse GME workforce.
Conclusions This qualitative study identified 5 themes that can inform and guide sponsoring institutions in promoting DEI.
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