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Genetically distinct variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged since the start of the COVID-19 pandemic. Over this period, we developed a rapid platform (R-20) for viral isolation and characterization using primary remnant diagnostic swabs. This, combined with quarantine testing and genomics surveillance, enabled the rapid isolation and characterization of all major SARS-CoV-2 variants circulating in Australia in 2021. Our platform facilitated viral variant isolation, rapid resolution of variant fitness using nasopharyngeal swabs and ranking of evasion of neutralizing antibodies. In late 2021, variant of concern Omicron (B1.1.529) emerged. Using our platform, we detected and characterized SARS-CoV-2 VOC Omicron. We show that Omicron effectively evades neutralization antibodies and has a different entry route that is TMPRSS2-independent. Our low-cost platform is available to all and can detect all variants of SARS-CoV-2 studied so far, with the main limitation being that our platform still requires appropriate biocontainment.

Immune cell deconvolution from molecular data. Relative proportions of immune cell subtypes are predicted from gene expression data using the Danaher method, and from methylation data using methylCIBERSORT. Differences between progressive and regressive groups are reported here.

Supplementary Methods

Before squamous cell lung cancer develops, precancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. Although recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of precancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using bronchoscopic biopsies from human subjects, we find that regressive carcinoma in situ lesions harbor more infiltrating immune cells than those that progress to cancer. Moreover, molecular profiling of these lesions identifies potential immune escape mechanisms specifically in those that progress to cancer: antigen presentation is impaired by genomic and epigenetic changes, CCL27–CCR10 signaling is upregulated, and the immunomodulator TNFSF9 is downregulated. Changes appear intrinsic to the carcinoma in situ lesions, as the adjacent stroma of progressive and regressive lesions are transcriptomically similar.Significance:Immune evasion is a hallmark of cancer. For the first time, this study identifies mechanisms by which precancerous lesions evade immune detection during the earliest stages of carcinogenesis and forms a basis for new therapeutic strategies that treat or prevent early-stage lung cancer.See related commentary by Krysan et al., p. 1442.This article is highlighted in the In This Issue feature, p. 1426

Purpose:Immune dysregulation is described in multiple myeloma. While preclinical models suggest a role for altered T-cell immunity in disease progression, the contribution of immune dysfunction to clinical outcomes remains unclear. We aimed to characterize marrow-infiltrating T cells in newly diagnosed patients and explore associations with outcomes of first-line therapy.Experimental Design:We undertook detailed characterization of T cells from bone marrow (BM) samples, focusing on immune checkpoints and features of immune dysfunction, correlating with clinical features and progression-free survival.Results:We found that patients with multiple myeloma had greater abundance of BM regulatory T cells (Tregs) which, in turn, expressed higher levels of the activation marker CD25 compared with healthy donors. Patients with higher frequencies of Tregs had shorter PFS and a distinct Treg immune checkpoint profile (increased PD-1, LAG-3) compared with patients with lower frequencies of Tregs. Analysis of CD4 and CD8 effectors revealed that low CD4effector (CD4eff):Treg ratio and increased frequency of PD-1–expressing CD4eff cells were independent predictors of early relapse over and above conventional risk factors, such as genetic risk and depth of response. Ex vivo functional analysis and RNA sequencing revealed that CD4 and CD8 cells from patients with greater abundance of CD4effPD-1+ cells displayed transcriptional and secretory features of dysfunction.Conclusions:BM-infiltrating T-cell subsets, specifically Tregs and PD-1–expressing CD4 effectors, negatively influence clinical outcomes in newly diagnosed patients. Pending confirmation in larger cohorts and further mechanistic work, these immune parameters may inform new risk models, and present potential targets for immunotherapeutic strategies.

Supplementary tables and figures

Huntington's disease (HD) belongs to protein misfolding disorders associated with polyglutamine (polyQ)-rich mutant huntingtin (mHtt) protein inclusions. Currently, it is indicated that the aggregation of polyQ-rich mHtt participates in neuronal toxicity and dysfunction. Here, we designed and synthesized a polyglutamine-specific gold nanoparticle (AuNP) complex, which specifically targeted mHtt and alleviated its toxicity. The polyglutamine-specific AuNPs were prepared by decorating the surface of AuNPs with an amphiphilic peptide (JLD1) consisting of both polyglutamine-binding sequences and negatively charged sequences. By applying the polyQ aggregation model system, we demonstrated that AuNPs-JLD1 dissociated the fibrillary aggregates from the polyQ peptide and reduced its β-sheet content in a concentration-dependent manner. By further integrating polyethyleneimine (PEI) onto AuNPs-JLD1, we generated a complex (AuNPs-JLD1-PEI). We showed that this complex could penetrate cells, bind to cytosolic mHtt proteins, dissociate mHtt inclusions, reduce mHtt oligomers, and ameliorate mHtt-induced toxicity. AuNPs-JLD1-PEI was also able to be transported to the brain and improved the functional deterioration in the HD

We report unidirectional transmission of micron-wide spin waves beams in a 55 nm thin YIG. We downscaled a chiral coupling technique implementing Ni80Fe20 nanowires arrays with different widths and lattice spacing to study the non-reciprocal transmission of exchange spin waves down to lambda = 80 nm. A full spin wave spectroscopy analysis of these high wavevector coupled-modes shows some difficulties to characterize their propagation properties, due to both the non-monotonous field dependence of the coupling efficiency, and also the inhomogeneous stray field from the nanowires., submitted to AIP advances as MMM proceeding article

Aims: This study evaluated the role of sodium, potassium, proline and soluble sugars accumulation in the ameliorative effect of an exogenous application of calcium on the detrimental effect of salinity on tomato plants. Study Design: The experiment was implemented as a Completely Randomized Design (RCD) with four treatments and three replications. Place and Duration of Study: The experiment was realized in a green house of the Faculty of Agronomical Sciences, University of Abomey-Calavi, Benin Republic from June to July 2020. Methodology: Three weeks old plants of the tomato cultivar “Padma” was submitted in pots to four treatments comprising the control (without NaCl); salt stress (120 mM NaCl) and a combination of 120 mM NaCl and exogenous application of 40 mM CaSO4 or Ca (NO3)2 by irrigation every two days. Plants growth, sodium (Na) and potassium (K) as well as proline and soluble sugars contents of leaves and roots were determined after two weeks. Results: Salt effect reduced significantly plant growth at P =.05, root K content at P =.05 and leaf K/Na ratio at P =.01 whereas it increased significantly leaf Na at P =.05 and root soluble sugars content at P =.05. The application of exogenous calcium (Ca) induced a significant amelioration of plant growth at P =.01 more marked with CaSO4 than with Ca (NO3)2. This treatment induced a significant decrease at P =.01 in leaf and root Na content and a significant increase at P =.05 in root K content only for CaSO4, a significant increase at P =.01 in leaf K/Na ratio and a significant increase at P =.01 in leaf and root proline content only for Ca(NO3)2. Conclusion: The ameliorative effect of both forms of calcium was due mainly to sodium (Na) exclusion from leaves and potassium (K) accumulation associated to a maintain of high K/Na ratio mainly in leaves. The importance of proline accumulation as an indicator of this ameliorative effect was associated only to Ca(NO3)2.

Objectifs : Le stress salin constitue un des stress environnementaux majeurs qui agit négativement sur la croissance des plantes. L’effet positif d’une application exogène de calcium et de potassium a été déterminé sur la croissance des plants de tomate soumis à la salinité. Méthodologie et résultats : Les plants de trois cultivars de tomate ont été exposés à six traitements comprenant le témoin sans NaCl ; 120 mM de NaCl et une combinaison entre 120 mM de NaCl et un apport de 40 mM de CaSO4 ; CaCl2 ; KNO3 ou K2SO4. La croissance des plantes a été déterminée après quinze jours d’exposition. L’application exogène de potassium n’a pas amélioré la croissance des plants stressés tandis que celle du calcium a atténué significativement les effets du NaCl sur les plantes du cultivar sensible Akikon. Aucun effet améliorateur n’a été observé chez les cultivars Tounvi et F1 Mongal. Conclusion et applications des résultats : Seule l’application exogène des deux formes de calcium a atténué les effets de la salinité sur la croissance des plantes du cultivar sensible Akikon. Le CaSO4 s’est révélé comme le meilleur composé pouvant atténuer les effets néfastes du sel chez la tomate, suivi par le CaCl2 notamment au niveau de la partie aérienne alors qu’au niveau de la partie racinaire, le CaCl2 a été plus efficace. Ainsi la réponse des plants de tomate cultivés sous stress salin à une application exogène de composés dépend non seulement du cultivar, de l’organe pris en compte mais aussi de la nature des composés apportés. Des études complémentaires sont nécessaires pour déterminer les mécanismes physiologiques impliqués dans l’effet améliorateur du calcium. Le CaSO4 et CaCl2 seront utiles pour la gestion de la salinité dans les zones de production de tomate Akikon. Mots clés : tolérance à la salinité, tomate, potassium, calcium, biomasse fraîche, biomasse sèche. Henry et al., J. Appl. Biosci. 2021 Réponse des plantes de tomate (Lycopersicon esculentum Mill.) cultivées sous stress salin a une application exogène de calcium et de potassium 16364 Response of tomato (Lycopersicon esculentum mill.) plants cultivated under salt stress to exogenous application of calcium and potassium ABSTRACT Aims: Salt stress is one of the major environmental stresses that have a negative effect on plant growth. The ameliorative effect of exogenous application of calcium and potassium was determined on the growth of tomato plants subjected to salinity. Methodology and results: Plants of three tomato cultivars were exposed to six treatments including the control without NaCl; 120 mM NaCl and a combination of 120 mM NaCl and an input of 40 mM CaSO4; CaCl2; KNO3 or K2SO4. Plant growth was determined after 15 days of exposure. The exogenous application of potassium did not improve the growth of stressed plants while that of calcium significantly attenuated the effects of NaCl on plants of the susceptible cultivar Akikon. No ameliorative effect was observed in cultivars Tounvi and F1 Mongal. Conclusions and applications of the results: Only exogenous application of both forms of calcium attenuated the effects of salinity on plant growth of the susceptible cultivar Akikon. CaSO4 has proven to be the best compound that can mitigate the harmful effects of salt in tomatoes, followed by CaCl2 especially in the aerial part, while in the root part, CaCl2 has been more effective. Thus, the response of tomato plants grown under salt stress to an exogenous application of compounds depends not only on the cultivar and the organ taken into account, but also on the nature of the compounds used. Further studies are needed to determine the physiological mechanisms involved in the ameliorative effect of calcium. CaSO4 and CaCl2 will be useful for the management of salinity in Akikon tomato production areas. Keywords: tolerance to salinity, tomato, potassium, calcium, fresh biomass, dry biomass.

Un aspecto crucial en la evolución del hombre lo constituyó el aprender a curar sus enfermedades a partir de lo que le proporcionaba la naturaleza; dentro de esos elementos se destacan predominantemente los vegetales. Así, el uso de las plantas ha sido un contribuyente importante al desarrollo de la farmacoterapia moderna. Debido a las condiciones físicas y químicas del ambiente marino, casi la totalidad de los organismos que habitan los mares exhiben una variedad de moléculas con cualidades estructurales y químicas únicas, producto del desarrollo de mecanismos bioquímicos y fisiológicos, que incluyen la producción de compuestos bioactivos para propósitos tales como la reproducción, comunicación, protección contra depredación, infecciones y competencia [4]. El uso de organismos marinos, y en especial las algas, para la producción de cosméticos se encuentra en auge en muchos países. Existe una gran variedad de productos cosméticos a nivel mundial, por la evidencia de las propiedades beneficiosas de las algas como promotores de la síntesis de fibras colágenas, antioxidantes, antiirritantes [6]. Específicamente, el extracto obtenido a partir de la angiosperma Thalassia testudinum denominado BM-21, ha sido el más estudiado y plantea un gran interés por su acción dermorregeneradora y potente capacidad antioxidante. Actualmente, las condiciones de obtención del extracto son: relación de material vegetal-volumen de disolvente 1:10, disolvente etanol al 50 %, temperatura de extracción 60 °C, tiempo de extracción 4 h. Si bien el BM-21 como materia prima ha resultado excelente por sus propiedades, desde el punto de vista tecnológico se necesita mejorar la etapa de extracción del proceso de producción con el objetivo de lograr una mayor extracción del producto en el menor tiempo posible.

Intratumoral regulatory T (Treg) cell abundance associates with diminished antitumor immunity and poor prognosis in human cancers. Recent work demonstrates that CD25, the high-affinity receptor subunit for interleukin (IL)-2, is a selective target for Treg depletion in mouse and human malignancies; however, anti-human CD25 antibodies have failed to deliver clinical responses against solid tumors due to bystander IL-2 receptor signaling blockade on effector T cells, which limits their antitumor activity. Here we demonstrate potent single-agent activity of anti-CD25 antibodies optimized to deplete Treg cells, while preserving IL-2-STAT5 signaling on effector T cells and show synergy with immune checkpoint blockade in vivo. Pre-clinical evaluation of an anti-human CD25 (RG6292) antibody with equivalent features demonstrates, in both nonhuman primates and humanized mouse models, efficient Treg cell depletion with no overt immune-related toxicities. Our data support the clinical development of RG6292 and evaluation of new combination therapies incorporating non-IL-2-blocking anti-CD25 antibodies in clinical studies. Quezada and colleagues develop improved anti-CD25 antibodies that preserve IL-2 signaling and enhance single-agent antitumor immunity and immunotherapy through specific and efficient Treg cell depletion.

Purpose: Immune dysregulation is described in multiple myeloma. While preclinical models suggest a role for altered T-cell immunity in disease progression, the contribution of immune dysfunction to clinical outcomes remains unclear. We aimed to characterize marrow-infiltrating T cells in newly diagnosed patients and explore associations with outcomes of first-line therapy. Experimental Design: We undertook detailed characterization of T cells from bone marrow (BM) samples, focusing on immune checkpoints and features of immune dysfunction, correlating with clinical features and progression-free survival. Results: We found that patients with multiple myeloma had greater abundance of BM regulatory T cells (Tregs) which, in turn, expressed higher levels of the activation marker CD25 compared with healthy donors. Patients with higher frequencies of Tregs had shorter PFS and a distinct Treg immune checkpoint profile (increased PD-1, LAG-3) compared with patients with lower frequencies of Tregs. Analysis of CD4 and CD8 effectors revealed that low CD4effector (CD4eff):Treg ratio and increased frequency of PD-1–expressing CD4eff cells were independent predictors of early relapse over and above conventional risk factors, such as genetic risk and depth of response. Ex vivo functional analysis and RNA sequencing revealed that CD4 and CD8 cells from patients with greater abundance of CD4effPD-1+ cells displayed transcriptional and secretory features of dysfunction. Conclusions: BM-infiltrating T-cell subsets, specifically Tregs and PD-1–expressing CD4 effectors, negatively influence clinical outcomes in newly diagnosed patients. Pending confirmation in larger cohorts and further mechanistic work, these immune parameters may inform new risk models, and present potential targets for immunotherapeutic strategies.

Micro-exons are exons of very small size (usually 3–30 nts). Some micro-exons are alternatively spliced. Their functions, regulation and evolution are largely unknown. Here, we present an example of an alternatively spliced 3 bp micro-exon (micro-Ex8) in the homothorax (hth) gene in Drosophila. Hth is involved in many developmental processes. It contains a MH domain and a TALE-class homeodomain (HD). It binds to another homeodomain Exd via its MH domain to promote the nuclear import of the Hth-Exd complex and serve as a cofactor for Hox proteins. The MH and HD domains in Hth as well as the HTh-Exd interaction are highly conserved in evolution. The alternatively spliced micro-exon lies between the exons encoding the MH and HD domains. We provide clear proof that the micro-Ex8 is produced by alternative splicing from a 48 bp full-length exon 8 (FL-Ex8) and the micro-Ex8 is the first three nt is FL-Ex8. We found that the micro-Ex8 is the ancient form and the 3 + 48 organization of alternatively spliced overlapping exons only emerged in the Schizophora group of Diptera and is absolutely conserved in this group. We then used several strategies to test the in vivo function of the two types of isoforms and found that the micro-Ex8 and FL-Ex8 isoforms have largely overlapping functions but also have non-redundant functions that are tissue-specific, which supports their strong evolutionary conservation. Since the different combinations of protein interaction of Hth with Exd and/or Hox can have different DNA target specificity, our finding of alternatively spliced isoforms adds to the spectrum of structural and functional diversity under developmental regulation.