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ABSTRACTThe coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has led to over 770 million cases and >6.9 million deaths worldwide. We identified a panel of human neutralizing monoclonal antibodies (mAbs) targeting the SARS-CoV-2 Spike protein using Harbour H2L2 transgenic mice immunized with Spike receptor-binding domain (RBD) (J. A. Duty, T. Kraus, H. Zhou, Y. Zhang, et al., Med 3:705–721, 2022, https://doi.org/10.1016/j.medj.2022.08.002). Representative antibodies from genetically distinct families were evaluated for the inhibition of replication-competent VSV expressing SARS-CoV-2 Spike (rcVSV-S) in the place of VSV-G. One mAb clone denoted FG-10A3 and its therapeutically modified version STI-9167 effectively inhibited infection and in vivo proliferation of early variants of SARS-CoV-2 including Omicron BA.1 and BA.2 and corresponding pseudoviruses and rcVSV-S variants (Duty et al.). To define the epitope of the broadly reactive FG-10A3 mAb, we generated mAb-resistant rcVSV-S virions and performed structural analysis of the antibody/antigen complex using cryo-electron microscopy (EM). FG-10A3/STI-9167 is a Class 1 antibody that prevents Spike-ACE2 binding by engaging a region within the Spike receptor binding motif. Sequencing of mAb-resistant rcVSV-S virions identified F486 as a critical residue for mAb neutralization, with structural analysis revealing that both the variable heavy and light chains of STI-9167 bound the disulfide-stabilized 470–490 loop at the Spike RBD tip. Furthermore, neutralization studies using rcVSV-S F486 point mutants and currently-circulating variants Omicron BA.5, XBB.1.5, and BQ.1.1 that contain a V or P at position 486 further supported the model in which residue 486 is an important residue for FG-10A3 inhibition. This work provides an experimental strategy to define the neutralizing capacity and limitations of mAb therapeutics against emerging SARS-CoV-2 variants.IMPORTANCEThe COVID-19 pandemic remains a significant public health concern for the global population; the development and characterization of therapeutics, especially ones that are broadly effective, will continue to be essential as severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) variants emerge. Neutralizing monoclonal antibodies remain an effective therapeutic strategy to prevent virus infection and spread so long as they recognize and interact with circulating variants. The epitope and binding specificity of a neutralizing anti-SARS-CoV-2 Spike receptor-binding domain antibody clone against many SARS-CoV-2 variants of concern were characterized by generating antibody-resistant virions coupled with cryo-EM structural analysis and VSV-spike neutralization studies. This workflow can serve to predict the efficacy of antibody therapeutics against emerging variants and inform the design of therapeutics and vaccines.

The emerging SARS-CoV-2 variants of concern (VOCs) exhibit enhanced transmission and immune escape, reducing the effectiveness of currently approved mRNA vaccines. To achieve wider coverage of VOCs, we first constructed a cohort of mRNAs harboring a furin cleavage mutation in the spike (S) protein of predominant VOCs, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2). The mutation abolished the cleavage between the S1 and S2 subunits. Systematic evaluation in vaccinated mice discovered that individual VOC mRNAs elicited strong neutralizing activity in a VOC-specific manner. In particular, the neutralizing antibodies (nAb) produced by immunization with Beta-Furin and Washington (WA)-Furin mRNAs showed potent cross-reactivity with other VOCs. However, neither mRNA elicited strong neutralizing activity against the Omicron variant. Hence, we further developed an Omicron-specific mRNA vaccine that restored protection against the original Omicron variant and some sublineages. Finally, to broaden the protection spectrum of the new Omicron mRNA vaccine, we engineered an mRNA-based chimeric immunogen by introducing the receptor-binding domain of Delta variant into the entire S antigen of Omicron. The resultant chimeric mRNA induced potent and broadly nAbs against Omicron and Delta, which paves the way to developing new vaccine candidates to target emerging variants in the future.

Morphogenetic gradients specify distinct cell populations within tissues. Originally, morphogens were conceived as substances that act on a static field of cells, yet cells usually move during development. Thus, the way cell fates are defined in moving cells remains a significant and largely unsolved problem. Here, we investigated this issue using spatial referencing of cells and 3D spatial statistics in the Drosophila blastoderm to reveal how cell density responds to morphogenetic activity. We show that the morphogen decapentaplegic (DPP) attracts cells towards its peak levels in the dorsal midline, whereas dorsal (DL) stalls them ventrally. We identified frazzled and GUK-holder as the downstream effectors regulated by these morphogens that constrict cells and provide the mechanical force necessary to draw cells dorsally. Surprisingly, GUKH and FRA modulate the DL and DPP gradient levels and this regulation creates a very precise mechanism of coordinating cell movement and fate specification.

Abstract Near‐term climate forcers (NTCFs) can influence climate via interaction with the Earth's radiative balance and include both aerosols and trace gas constituents of the atmosphere (such as methane and ozone). Two of the principal NTCFs, aerosols (particulate matter) and tropospheric ozone (O3), can also affect local air quality when present in the lower levels of the atmosphere. Previous studies have shown that mitigation of NTCFs has the potential to improve air quality and reduce the rate of surface warming induced by long‐lived greenhouse gases. Here, we assess the combined air quality and climate impacts from changes in NTCFs under numerous different future mitigation scenarios, relative to a future reference scenario, that were conducted by a single Earth system model (UKESM1) as part of the Aerosol and Chemistry Model Intercomparison Project (AerChemMIP). Co‐benefits to both global air quality and climate are only achieved in the future scenario with strong mitigation measures applied to all NTCFs, particularly aerosols and methane, with penalties identified for inaction. When compared to the combined NTCF mitigation scenario, analysis of individual mitigation scenarios shows that there are important non‐linearities and interactions between NTCFs (e.g., aerosols and clouds). If only aerosol components are mitigated, there are still benefits to air quality but detrimental impacts on climate, particularly at the regional scale. In addition, other changes in future land‐use and climate could have important impacts on regional NTCFs, which should be considered when designing future mitigation measures to anthropogenic emissions.

Abstract In 2013, scientists implemented a binational exchange for emergency planners and responders in communities near Nevado del Ruiz in Colombia and volcanoes of the Cascade Range of the United States (US). This program was designed to promote understanding of volcanic disasters and effective mitigation options, motivate participants to strengthen emergency planning efforts, and promote trust-building among participants. The 2013 Binational Exchange was funded by the Volcano Disaster Assistance Program (VDAP), a joint U.S. Geological Survey (USGS)—U.S. Agency for International Development (USAID) program. During a week-long visit to Colombian emergency response agencies, Nevado del Ruiz, and lahar-destroyed ruins of the city of Armero and the region of Viejo Rio Claro, US participants became familiar with Colombian counterparts who have had recent and frequent experiences addressing volcanic crises. Aging survivors and authorities of the Nevado del Ruiz catastrophe of 1985 gave participants first-hand accounts, and ideas for improved preparedness and response. While in the US, Colombian participants observed emergency response capabilities and facilities, and received training in systems of incident command. Colombians made presentations to the US public and officials about the similarities of lahar risks in both nations. This article describes the 2013 Binational Exchange as an experiential learning event and uses results of post-exchange discussions and interviews as evidence of steps achieved within the learning process. Six years hence, this article provides examples of progress with volcano hazards mitigation in both nations. The article offers the binational exchange model as an effective tool that employs both experiential learning and socialization of participants to create a highly motivating and effective learning environment.

Iatrogenic common femoral artery pseudoaneurysm is a well-known vascular access complication of angiography and transfemoral intervention. Thrombin injection is a well-accepted technique in treating these pseudoaneurysms but possess a significant risk of distal lower extremity thrombosis leading to severe consequences. Several case reports described the novel approach to closing these pseudoaneurysms via a retrograde deployment of an Angio-Seal vascular closure device. We describe a case of a successful treatment of refractory iatrogenic femoral artery pseudoaneurysm using Amplatzer vascular plugs following unsuccessful retrograde deployment of an Angio-Seal vascular closure device.

Abstract Background Medial humeral epicondyle fractures of the elbow are one of the most common injuries in childhood and often require surgery. There are currently no standardised outcome measures to assess progress after an elbow injury in a child. Wide variation in currently reported outcomes makes comparison of treatment difficult. This study aims to identify outcome measures that have previously been reported in studies evaluating the management of medial epicondyle fractures in children and to facilitate the development of a consensus core outcome set (COS) suitable for use in all future studies of medial humeral epicondyle fractures in children. Methods/design This study will include a systematic review of the academic literature to identify a list of outcome measures that have previously been reported. The list of outcome measures will be used in a consensus setting exercise with focus groups of key stakeholders to identify key outcomes. A Delphi process to include two rounds will then be used to define the most important outcomes to all stakeholders forming the COS. Discussion Core outcomes represent the minimum expected data reported for a specific condition and will improve the quality of future studies reducing bias, allowing easier comparison and enhancing opportunities for larger meta-analysis. It is anticipated that this COS will form part of the feasibility to a National Institute for Health Research (NIHR) Health Technology Assessment (HTA)-funded trial concerning the management of elbow fractures in children. Trial registration Core Outcome Measures in Effectiveness Trials Initiative (COMET), registration number:949. Registered on 17 January 2017. Prospero International prospective register of systematic reviews, registration number: CRD 42017057912. Registered on 16 April 2017.

Background: Radioembolization with yttrium microspheres is an established therapeutic modality for primary and secondary hepatic malignancies, with studies demonstrating improved overall survival. There remains a paucity of data on cholecystitis as a complication of radioembolization. We describe a small series of patients who developed cholecystitis as a result of radioembolization. Methods: Patients who had developed cholecystitis as a complication of radioembolization in our institution between 2001 and 2012 were retrospectively reviewed. Patient demographics, cancer details including treatment history, and procedural details of radioembolization and complications of cholecystitis were collected. Results: Of 74 patients who underwent radioembolization using yttrium-90emitting microspheres, four (5.4%) presented with acute cholecystitis as a result of their treatment. All patients presented over 4 weeks following radioembolization and did not settle with conservative treatment. At surgery, the gallbladder was fibrotic and contracted in all cases making surgery difficult. Conclusion: The incidence of symptomatic radiation cholecystitis after radioembolization is low, and prophylactic cholecystectomy is not routinely recommended for patients undergoing radioembolization. Radiation cholecystitis should be suspected in patients presenting with symptoms of biliary colic or cholecystitis following radioembolization. Early cholecystectomy can be considered in patients undergoing surgery for other indications, especially in high-risk surgical patients in whom there is a high likelihood of radioembolization in the future as they do not respond to conservative treatment.

This paper examines gender role messages conveyed in Cameroonian folktales. Folktales promote women's rivalry and mask men's culpability in oppressing women by setting the stage for their jealousy, enmity and competition. Attention is drawn away from men's wrong doing toward women by depicting women as conniving evil doers who sometimes use men as pawns to implement their plots. The women are deserving of punishment while men go free from any penalty. Dichotomous representations of women encourage women's rivalry and subordination to men. These repeated teachings convey that women are dangerous and that 'good women' embody all those characteristics that exalt and benefit men. Rivalry between women is augmented by men's comparisons between the 'good woman' and 'bad woman.' If women want to survive in a man's world, the message is unambiguous - be a 'good woman' by exemplifying absolute submissiveness and staying removed and disunited from their sisters.

Neuregulins are a family of growth factors with potent neuroprotective properties. We recently demonstrated that neuregulin-1 blocked delayed neuronal death following focal ischemic stroke in the rat. Focal ischemia results in the release of pro-inflammatory cytokines that produce profound changes in gene expression and contribute to cell death associated with stroke. Inflammatory and stress mediators are involved in the pathogenesis of focal ischemic brain damage. We examined whether neuregulin-1 can influence inflammatory and stress gene expression in the rat brain following transient middle cerebral artery occlusion (MCAO). In this study, we compared gene expression profiles in animals treated with neuregulin-1β (NRG-1) or vehicle followed by MCAO. We used the Affymetrix GeneChip system to analyze gene expression in focal ischemia of the rat brain. Several inflammatory and stress genes were significantly induced following MCAO compared to sham controls including heat shock protein-70 (HSP70), interleukin-1β, and macrophage chemotattractant protein-1 (JE/MCP-1). Treatment with NRG-1 attenuated the expression of many of these genes by 50% or more. In vitro studies demonstrated that NRG-1 suppressed inflammatory gene expression in activated macrophages. NRG-1 also prevented neuronal death induced by oxygen-glucose deprivation in a rat neuroblastoma cell line, suggesting that NRG-1 may have both direct and indirect neuroprotective capacity. These results demonstrate that NRG-1 can regulate inflammatory and stress gene expression and may give new insight to the molecular mechanisms involved in the neuroprotective role of neuregulins in stroke.

Italo Calvino has a widely recognized and significant position in Italian literature and culture as one of the masters of twentieth-century Italian letters, recognized for his intensely visual imagination and geometric formalism. This position, however, might actually understate Calvino’s significance, because his influence has been at least as significant outside of Italy as inside, and larger outside of literature than inside (Invisible Cities, in particular, has had an enormous influence in art, architecture, urban planning, design, and even social services offered in urban spaces). A useful model for thinking about transcultural and transmedial influence might be the notion of resonance, in which a sound (Calvino’s writing in this case) reverberates in an increasingly large and complex cultural space — such a model might be particularly attractive when it comes to Calvino, since it has the potential to reframe the attention to the visual and the geometric. This article looks to one particular example of this cultural resonance: Lisa Mezzacappa’s 2020 jazz suite of Calvino’s Cosmicomics. Jazz might seem like an unusual way of conceptualizing Calvino, but in Un ottimista in America, Calvino himself suggested that jazz has a particular and positive capacity to think through cultural dilemmas without “crystallizing” into a static and unproductive image (a point he would also make in one of his cosmicomic stories, tellingly entitled “I cristalli”). Indeed, jazz allows us a different way to hear Calvino: playful, improvisational, and sensual. Looking primarily at one track from Mezzacappa’s suite, “The Form of Space,” I contend that her adaptation encourages us to hear Calvino story as a critique of the purely cerebral, visual and geometric; the music instead gestures toward a subject who is neurotic, perverse and unpredictable. The improvisational nature of jazz and the Lucretian geometry of spacetime both suggest that the supposedly rational and composed subject might swerve out of the predictable straight line into surprising new territory that is boisterous, risky and remarkably open.

Book review

Adequate yearly progress (AYP) on No Child Left Behind criteria was examined for a randomly selected sample of districts that qualify for the Rural Education Achievement Program (REAP). The sample involved 10% of districts that were eligible for the Small Rural Schools Achievement (SRSA) program and 10% that were eligible for the Rural and Low-income Schools (RLIS) program. Based on district reports, nearly 80% of SRSA schools made AYP, 11% failed, and 11% did not have adequate data. For schools in the RLIS program, districts reported that 65% made AYP, 29% failed, and 6% did not report adequate data. The SRSA and RLIS samples had different patterns for the categories of students that did not make AYP. Also, SRSA and RLIS districts were differentially distributed across the United States. Implications for interventions are discussed.

OFFICE POLITICS WILFRID SHEED 320pp. McNally Editions. $18. If Joseph Heller, Henry James, Evelyn Waugh and Kingsley Amis collaborated on a scathing novel of cubicle mutiny, it might resemble Wilfrid [...]

ANTONIO SKARMETA The Names of the Things That Were There Trans. Curtis Bauer. New York. Other Press. 2023.352 pages. THE THIRTEEN EXEMPLARY character-driven stories in Chilean author Antonio Skarmeta's The [...]

Domenico Starnone The Mortal and Immortal Life of the Girl from Milan Trans. Oonagh Stransky. New York. Europa. 2024. 144 pages. LIFELONG REPERCUSSIONS of an obsessive, unrequited love mingle with [...]