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The Spike protein of SARS-CoV-2 has a C-terminal cytoplasmic tail. Here the authors show that this tail binds trafficking machinery via sequences that appear optimised to ensure that Spike accumulates at the site of viral budding in the Golgi but that some can also traffic to the cell surface to induce syncytia formation.

In early 2020, at first surge of the coronavirus disease 2019 (COVID-19) pandemic, many health care workers (HCW) were re-deployed to critical care environments to support intensive care teams looking after patients with severe COVID-19. There was considerable anxiety of increased risk of COVID-19 for these staff. To determine whether critical care HCW were at increased risk of hospital acquired infection, we explored the relationship between workplace, patient facing role and evidence of immune exposure to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within a quaternary hospital providing a regional critical care response. Routine viral surveillance was not available at this time.

Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is a negative-sense RNA virus spread by Hyalomma genus ticks across Europe, Asia, and Africa. CCHF disease begins as a non-specific febrile illness which may progress into a severe hemorrhagic disease with no widely approved or highly efficacious interventions currently available. Recently, we reported a self-replicating, alphavirus-based RNA vaccine that expresses the CCHFV nucleoprotein and is protective against lethal CCHFV disease in mice. This vaccine induces high titers of non-neutralizing anti-NP antibodies and we show here that protection does not require Fc-gamma receptors or complement. Instead, vaccinated mice deficient in the intracellular Fc-receptor TRIM21 were unable to control the infection despite mounting robust CCHFV-specific immunity. We also show that passive transfer of NP-immune sera confers significant TRIM21-dependent protection against lethal CCHFV challenge. Together our data identifies TRIM21-mediated mechanisms as the Fc effector function of protective antibodies against the CCHFV NP and provides mechanistic insight into how vaccines against the CCHFV NP confer protection. Non-neutralizing antibodies against the nucleoprotein (NP) of Crimean-Congo hemorrhagic fever virus are protective against lethal challenge in mice. Here, the authors show that these anti-NP antibodies protect through the intracellular antibody receptor TRIM21 and that protection is independent of T cells. [ABSTRACT FROM AUTHOR]

Academic review, promotion, and tenure processes place a premium on frequent publication in high‐impact factor (IF) journals. However, conservation often relies on species‐specific information that is unlikely to have the broad appeal needed for high‐IF journals. Instead, this information is often distributed in low‐IF, taxa‐ and region‐specific journals. This suggests a potential mismatch between the incentives for academic researchers and the scientific needs of conservation implementation. To explore this mismatch, we looked at federal implementation of the United States Endangered Species Act (ESA), which requires the use of the “best available science” to list a species as endangered or threatened and thus receive powerful legal protections. In assessing the relationship between academic sources of this “best available science” and ESA implementation, we looked at the 13,292 sources (e.g., academic journals, books, reports, regulations, personal communications, etc.) cited by the second Obama administration (2012–2016) across all ESA listings. We compared the IFs of all 4836 journals that published peer‐reviewed papers cited in these listings against their citation frequency in ESA listings to determine whether a journal's IF varied in proportion with its contribution to federal conservation. Most of the peer‐reviewed academic articles referenced in ESA listings came from low‐IF or no‐IF journals that tended to focus on specific taxa or regions. Although we support continued attention to cutting‐edge, multidisciplinary science for its ability to chart new pathways and paradigms, our findings stress the need to value and fund the taxa‐ and region‐specific science that underpins actionable conservation laws. [ABSTRACT FROM AUTHOR]

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016–2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence‐based guidelines in anticipation of disease‐specific therapies. [ABSTRACT FROM AUTHOR]

Our study (NCT04800133) aimed to determine the safety and immunogenicity in patients with IEIs receiving a 3-dose primary series of mRNA vaccine BNT162b2 (age 12+) or inactivated whole-virion vaccine CoronaVac (age 3+) in Hong Kong, including Omicron BA.1 neutralization, in a nonrandomized manner. Intradermal vaccination was also studied. Thirty-nine patients were vaccinated, including 16 with homologous intramuscular 0.3ml BNT162b2 and 17 with homologous intramuscular 0.5ml CoronaVac. Two patients received 3 doses of intradermal 0.5ml CoronaVac, and 4 patients received 2 doses of intramuscular BNT162b2 and the third dose with intradermal BNT162b2. No safety concerns were identified. Inadequate S-RBD IgG and surrogate virus neutralization responses were found after 2 doses in patients with humoral immunodeficiencies and especially so against BA.1. Dose 3 of either vaccine increased S-RBD IgG response. T cell responses against SARS-CoV-2 antigens were detected in vaccinated IEI patients by intracellular cytokine staining on flow cytometry. Intradermal third dose vaccine led to high antibody response in 4 patients. The primary vaccination series of BNT162b2 and CoronaVac in adults and children with IEIs should include 3 doses for optimal immunogenicity.

Abstract A fundamental property of infectious agents is their particulate nature: infectivity arises from independently-acting particles rather than as a result of collective action. Assemblies of the protein tau can exhibit seeding behaviour, potentially underlying the apparent spread of tau aggregation in many neurodegenerative diseases. Here we ask whether tau assemblies share with classical pathogens the characteristic of particulate behaviour. We used organotypic hippocampal slice cultures from P301S tau transgenic mice in order to precisely control the concentration of extracellular tau assemblies in neural tissue. Whilst untreated slices displayed no overt signs of pathology, exposure to recombinant tau assemblies could result in the formation of intraneuronal, hyperphosphorylated tau structures. However, seeding ability of tau assemblies did not titrate in a one-hit manner in neural tissue. The results suggest that seeding behaviour of tau arises at high concentrations, with implications for the interpretation of high-dose intracranial challenge experiments and the possible contribution of seeded aggregation to human disease.

The mechanism by which RING E3-anchored ubiquitin chains are formed is not well understood. Here, the authors solve a crystal structure of the RING E3 enzyme TRIM21 trapped in the process of self-anchored chain elongation and provide biochemical and cellular insights into the mechanism of ubiquitin conjugation.

KEOPS is an evolutionary conserved complex with a core of four core subunits—Pcc1, Kae1, Bud32 and Cgi121—that catalyzes the universal and essential tRNA modification N6-threonylcarbamoyl adenosine (t6A). Here the authors describe a Cgi121-tRNA crystal structure and new composite model of the KEOPS holo-enzyme-substrate complex that shed light on the t6A catalytic cycle and its regulation.

Scientific professional societies are reviewing diversity, equity, and inclusion (DEI) practices and policies in response to recent calls for much-needed change. Organizations like scientific professional societies contribute to establishing disciplinary norms, and can influence the diversity of disciplinary workforces in multiple ways through both action and inaction. This paper examines these issues using the American Elasmobranch Society (AES), a medium-sized professional scientific society, as a case study. It consists of three parts: (1) an analysis of the demographics of AES members, leaders, and award winners; (2) an evaluation of a diversity initiative created by the society which includes a survey of program alumni focusing on potential improvements to the program; and (3) a synthesis of recommendations of steps that AES and similarly sized societies can take to better support DEI goals. AES’s membership in recent years is more than half women, but 71.5% of all leadership positions in the Society’s history (including all but two Presidents) have been held by men since the society was founded in 1983. AES’s membership has significantly fewer Black/African-American members than the United States scientific workforce overall, with just 1 member out of over 400 identifying as Black in 2019, and 86.6% of Society leadership positions have been held by white-presenting members. The Society’s diversity initiative has led to some limited professional benefits for awardees, but could benefit from additional resources and support to enact suggested expansions and improvements. We provide a series of actionable recommendations that will make the annual meetings of societies like AES, and the field of chondrichthyan science, safer and more inclusive.