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Imaging plays an important role in the evaluation of the urologic organs. Radiographs, fluoroscopy, ultrasound, computed tomography, and MRI are all modalities that can be used to answer various clinical questions. In this article we provide an overview of the most common imaging examinations performed using these modalities to assess the urologic structures.

A spinal cord injury (SCI) disrupts the neuronal projections from the brain to the region of the spinal cord that produces walking, leading to various degrees of paralysis. Here, we aimed to identify brain regions that steer the recovery of walking after incomplete SCI and that could be targeted to augment this recovery. To uncover these regions, we constructed a space–time brain-wide atlas of transcriptionally active and spinal cord-projecting neurons underlying the recovery of walking after incomplete SCI. Unexpectedly, interrogation of this atlas nominated the lateral hypothalamus (LH). We demonstrate that glutamatergic neurons located in the LH (LHVglut2) contribute to the recovery of walking after incomplete SCI and that augmenting their activity improves walking. We translated this discovery into a deep brain stimulation therapy of the LH (DBSLH) that immediately augmented walking in mice and rats with SCI and durably increased recovery through the reorganization of residual lumbar-terminating projections from brainstem neurons. A pilot clinical study showed that DBSLHimmediately improved walking in two participants with incomplete SCI and, in conjunction with rehabilitation, mediated functional recovery that persisted when DBSLHwas turned off. There were no serious adverse events related to DBSLH. These results highlight the potential of targeting specific brain regions to maximize the engagement of spinal cord-projecting neurons in the recovery of neurological functions after SCI. Further trials must establish the safety and efficacy profile of DBSLH, including potential changes in body weight, psychological status, hormonal profiles and autonomic functions.

An energy saving behavior is presented for autonomous underwater vehicles (AUVs) that uses greedy control decisions to take advantage of vertical gradients in ocean currents. The behavior relies on a dynamic vehicle model for motion and power consumption and environmental information that can be realistically obtained and processed onboard. Vehicle model parameters are consistent with a 12.75-in-diameter propeller-driven AUV. Simulation results are presented using a two-year tidally resolving ocean circulation model over three spatially distinct transits in the Southern California Bight. The energy saving behavior is compared to the common practice of transiting at fixed depth, as well as a “best case” scenario in which a vehicle has knowledge of the full-depth ocean current profile at its local position. The proposed behavior saves between 3% and 10% in energy expenditure depending on the vehicle's initial launch depth. On average, it is most efficient to initialize the vehicle at depths corresponding to the base of the surface oceanic mixed layer. Finally, a reduced order approximation of the optimal planning solution shows that the vehicle's depth choices oscillate with dominant tidal constituents for the region.

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection1,2, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases.

CD4+T cells recognize peptide antigens presented on class II major histocompatibility complex (MHC-II) molecules to carry out their function. The remarkable diversity of T cell receptor sequences and lack of antigen discovery approaches for MHC-II make profiling the specificities of CD4+T cells challenging. We have expanded our platform of signaling and antigen-presenting bifunctional receptors to encode MHC-II molecules presenting covalently linked peptides (SABR-IIs) for CD4+T cell antigen discovery. SABR-IIs can present epitopes to CD4+T cells and induce signaling upon their recognition, allowing a readable output. Furthermore, the SABR-II design is modular in signaling and deployment to T cells and B cells. Here, we demonstrate that SABR-IIs libraries presenting endogenous and non-contiguous epitopes can be used for antigen discovery in the context of type 1 diabetes. SABR-II libraries provide a rapid, flexible, scalable and versatile approach for de novo identification of CD4+T cell ligands from single-cell RNA sequencing data using experimental and computational approaches.

The article titled "HAVE WE SAVED ENOUGH LAND IN THE RIGHT PLACES?" is a report from a collaboration between Native Plant Trust and The Nature Conservancy. The report examines the conservation efforts in New England and their impact on plant diversity and preventing plant extinctions. The report concludes that more needs to be done to protect land in the right places to achieve these goals. It provides a scientific framework, roadmap, and mapping tool for conservation action and land protection. The report also recommends focusing on proportional representation of habitats, enhancing the level of protection for already secured lands, and implementing strategies like seed banking and assisted migration. The full report and summaries for each New England state can be found on the Native Plant Trust website. [Extracted from the article]

Here, we introduce the Tabulae Paralytica—a compilation of four atlases of spinal cord injury (SCI) comprising a single-nucleus transcriptome atlas of half a million cells, a multiome atlas pairing transcriptomic and epigenomic measurements within the same nuclei, and two spatial transcriptomic atlases of the injured spinal cord spanning four spatial and temporal dimensions. We integrated these atlases into a common framework to dissect the molecular logic that governs the responses to injury within the spinal cord1. The Tabulae Paralyticauncovered new biological principles that dictate the consequences of SCI, including conserved and divergent neuronal responses to injury; the priming of specific neuronal subpopulations to upregulate circuit-reorganizing programs after injury; an inverse relationship between neuronal stress responses and the activation of circuit reorganization programs; the necessity of re-establishing a tripartite neuroprotective barrier between immune-privileged and extra-neural environments after SCI and a failure to form this barrier in old mice. We leveraged the Tabulae Paralyticato develop a rejuvenative gene therapy that re-established this tripartite barrier, and restored the natural recovery of walking after paralysis in old mice. The Tabulae Paralyticaprovides a window into the pathobiology of SCI, while establishing a framework for integrating multimodal, genome-scale measurements in four dimensions to study biology and medicine.

We demonstrate the feasibility of an optical sensor that can monitor changes in dissolved sodium oxide levels [<10 parts per million (ppm)] in molten sodium. Sodium is used as a coolant in some Generation IV nuclear reactors known as sodium fast reactors (SFRs), where isolating the metal from oxygen is paramount for safe and reliable operation. The sensor presented here provides a significantly improved response time compared to the well-established plugging meter technique used in molten sodium systems for measuring dissolved oxygen concentrations of a few ppm. The sensing approach presented is promising as it can overcome several critical limitations of the plugging meter, such as equipment size, measurement time, and power consumption. It can also be a valuable tool in understanding impurity precipitation, deposition, and growth mechanisms in molten sodium. Index Terms— Corrosion tests, impurity detection, molten sodium, optical fiber, optical sensor, sodium fast reactors (SFRs), sodium oxide.

ABSTRACTThe Cook Strait click beetle (Amychus granulatus) is found only in five offshore island refugia in New Zealand. We estimated their elevational distribution, population density, and habitat associations within sampling plots on Te Pākeka/Maud Island using mark-recapture methods. We marked and recaptured individual beetles during seven nightly surveys in November 2020 and recorded a range of environmental variables to better understand their habitat associations. Our surveys confirmed the presence of beetles across the island's elevational range, but population densities appeared highest at lower elevations. Based on recaptures, we estimated a mean density of 892 beetles/ha (95% CI: 556–1620) in one large, low-elevation plot and 575 beetles/ha (95% CI: 230–1960) across the remaining plots. Temperature may have affected nightly beetle activity, and hence also capture probability. Habitat assessments suggest the abundance of mahoe (Melicytus ramiflorus), and daytime refugia in tree cavities or rocky areas positively affected beetle counts. Our results provide the first robust population estimates for this endemic species. The apparent patchy distribution pattern we observed and its possible link to environmental variables have the potential to inform on conservation management including future translocations of Cook Strait click beetles to predator-free locations where suitable habitat exists.

The article titled "TRAILGRAMS" in Mountain Bike Action features letters from readers discussing various topics related to mountain biking. One reader expresses the need for more diversity and inclusion in the magazine, highlighting the presence of African Americans, Latinos, and other minorities in the sport. Another reader shares their enthusiasm for finding treasures while mountain biking. A third reader discusses the issue of trail etiquette and the negative experiences they have had with certain mountain bikers. Lastly, a reader from Prescott, Arizona, raises concerns about the classification and access of electric-assist mountain bikes on public lands. The editor responds to the readers' letters, providing information and opinions on the topics discussed. [Extracted from the article]

Differences in perceptions of disability between students and administrators can play a role in youth’s educational experience. This study used data from a cluster randomized controlled trial (C-RCT) of the Self-Determined Learning Model of Instruction (SDLMI) to first compare student self-report of disability status to matched administrative data and second to examine the impact of the data source utilized on trial outcomes. The findings demonstrate substantive gaps between self-reports and administrative reports of disability. While some differences might be expected, the size of the differences is notable, especially given that many students identified as having an Individualized Education Program in administrative data did not self-identify as receiving services or having a disability. The findings advance understanding of discrepancies in self-reported disability and administrative data in secondary intervention research. We also found the interpretation of group differences (students with vs. without disabilities) on trial outcomes was sensitive to the source of the data (self vs. administrative) used to establish disability status. This finding can inform future research and policy, as the data source selected to define disability populations across research studies likely has substantive impacts on conclusions drawn about the impact of interventions on students with disabilities. We cannot identify all the factors driving these differences. Nonetheless, the findings underscore the importance of providing clarity about decisions made in defining disability populations in intervention research.

Rust fungi (Pucciniales, Basidiomycota) are a species-rich (ca. 8000 species), globally distributed order of obligate plant pathogens. Rust species are host-specific, and as a group they cause disease on many of our most economically and/or ecologically significant plants. As such, the ability to accurately and rapidly identify these fungi is of particular interest to mycologists, botanists, agricultural scientists, farmers, quarantine officials, and associated stakeholders. However, the complexities of the rust life cycle, which may include production of up to five different spore types and alternation between two unrelated host species, have made standard identifications, especially of less-documented spore states or alternate hosts, extremely difficult. The Arthur Fungarium (PUR) at Purdue University is home to one of the most comprehensive collections of rust fungi in the world. Using material vouchered in PUR supplemented with fresh collections we generated DNA barcodes of the 28S ribosomal repeat from > 3700 rust fungal specimens. Barcoded material spans 120 genera and > 1100 species, most represented by several replicate sequences. Barcodes and associated metadata are hosted in a publicly accessible, BLAST searchable database called Rust HUBB (Herbarium-based Universal Barcode Blast) and will be continuously updated.

Natural gas is a critical part of the world’s energy supply and plays an important role in the transition to lower-carbon energy sources. The industry’s ability to process natural gas safely and efficiently will continue to rely on an accurate understanding of feed gas composition and contaminants, particularly in enabling future developments via existing infrastructure. Mercury is toxic to organisms, highly volatile and produced from hydrocarbon basins globally. Trace mercury concentrations in the hydrocarbon stream can potentially introduce liquid metal embrittlement hazards to industrial equipment, including cryogenic heat exchangers used to refrigerate liquefied natural gas. Inaccurate measurement of mercury levels can lead to adverse impacts measurable across the areas of health, process safety, environment, operations, waste disposal and decommissioning. Worldwide, significant project cost overruns and processing incidents have resulted from the uncertainty of mercury concentrations in hydrocarbon streams. Successful mercury management ideally begins early in a project’s lifecycle with development decisions informed by accurate measurement of mercury concentrations from reservoirs. Historically, this has been problematic, as mercury contamination and scavenging often result in a large range of uncertainty. The results from a multi-company collaborative study to reduce mercury uncertainty with new downhole sampling techniques will be shared in a case study, including production insights from the Julimar Field, west coast of Australia. The recommendations, procedures and operational best practices discussed will be applicable across the industry and beneficial to any party considering the impact of mercury in the development and processing of natural gas resources.

Understanding the anatomy, injury patterns, and surgical procedures is essential for image interpretation. While direct evaluation of the rotator cuff cannot be made, radiographs of the shoulder provide the initial evaluation of the osseous abnormalities associated with rotator cuff impingement. MR imaging is considered the study of choice for the evaluation of the shoulder because of the comprehensive assessment of both bone and soft-tissue abnormalities. MR can accurately evaluate the size and shape of tendon tears, tendon tear retraction, and tendon and muscle quality. Computed tomography is an excellent modality for the evaluation of osseous detail and detection of gas and calcium deposition; however, conventional CT is much less sensitive for bone marrow edema detection and soft tissue detail of the rotator cuff. Ultrasound can assess the rotator cuff with results similar to MRI, but cannot evaluate osseous structures.

Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.

A spinal cord injury disrupts communication between the brain and the circuits in the spinal cord that regulate neurological functions. The consequences are permanent paralysis, loss of sensation and debilitating dysautonomia. However, the majority of circuits located above and below the injury remain anatomically intact, and these circuits can reorganize naturally to improve function. In addition, various neuromodulation therapies have tapped into these processes to further augment recovery. Emerging research is illuminating the requirements to reconstitute damaged circuits. Here, we summarize these natural and targeted reorganizations of circuits after a spinal cord injury. We also advocate for new concepts of reorganizing circuits informed by multi-omic single-cell atlases of recovery from injury. These atlases will uncover the molecular logic that governs the selection of 'recovery-organizing' neuronal subpopulations, and are poised to herald a new era in spinal cord medicine.

AbstractThe objective of the Versatile Test Reactor (VTR) is to enable testing of advanced reactor fuels and materials in a fast spectrum neutron environment. Internal cartridge loop testing capabilities are being developed that will allow the cartridge coolant to be isolated from the reactor coolant. This approach will allow various cartridge coolants to be investigated, thereby maximizing testing capability. A sodium cartridge loop testing capability is being developed by a team that includes Argonne National Laboratory (Argonne) as the laboratory partner, Framatome Inc. as the industrial partner, and Purdue University along with the University of Wisconsin–Madison as university partners. Specific elements of the current work include overall cartridge loop design development that is being led by Framatome, Inc. Coolant chemistry monitoring and control are key elements of any high-pedigree irradiation testing capability; the University of Wisconsin is leading this effort by developing and experimentally verifying methods for achieving this capability in pile. Purdue University is developing a scaling methodology, and on that basis, a thermal-hydraulic testing capability to validate fluid flow and heat transfer models for the cartridge that will be used to support design and safety analysis activities. Argonne has focused on developing and testing technologies specifically targeted at simplifying VTR operations, as well as developing modeling tools to support cartridge loop design and safety analysis. The purpose of this paper is to summarize the current status of the sodium fast reactor cartridge development, including details on the cartridge functional requirements, physical design, chemistry control, operations, and safety.

Dried blood spots (DBSs) provide an alternative sample input for serologic testing. We evaluated DBSs for the ARCHITECT®hepatitis B surface antigen (HBsAg) NEXT, hepatitis B e-antigen (HBeAg), anti-hepatitis B core antigen (anti-HBc II), HIV antigen/antibody (Ag/Ab) Combo and AdviseDx SARS-CoV-2 IgG II assays. Assay performance with DBSs was assessed with or without assay modification and compared with on-market assay with plasma samples. DBS stability was also determined. HBsAg NEXT and HIV Ag/Ab Combo assays using DBSs showed sensitivity and specificity comparable to that of on-market assays. Modified HBeAg, anti-HBc II and SARS-CoV-2 IgG II DBS assays achieved performance comparable to on-market assays. Use of DBSs as input for high-throughput serologic assays is expected to have significant implications for improving population surveillance and increasing access to diagnostic testing.

Numerous abdominal manifestations have been reported in patients with coronavirus disease 2019 (COVID-19), including involvement of the luminal gastrointestinal (GI) tract, hepatobiliary system, pancreas, kidneys, spleen, and blood vessels. Although most of the associated radiological abnormalities are nonspecific without distinguishing imaging features to suggest COVID-19, unique presentations such as findings of bowel ischemia preceding gross findings of bowel necrosis have been reported. Awareness of the spectrum of abdominal manifestations of COVID-19 allows radiologists to optimize their search pattern and to raise the possibility of this etiology when appropriate. Awareness of the possible abdominal manifestations of COVID-19 should enhance detection by radiologists and improve patient care. This review provides a comprehensive overview with illustrative imaging examples of COVID-19 in the abdomen.

Although many studies have examined how improvements in wastewater treatment impact river nutrient concentrations and loads, there has been much less focus on measuring river metabolism to evaluate the wider aquatic ecosystem benefits of reducing nutrient inputs to rivers. The objectives of this study were to evaluate the effects of enhanced wastewater treatment (nitrification) on river metabolism in the Grand River, Canada's largest river draining into Lake Erie. Metabolic fingerprints and regimes (calculated from high‐frequency dissolved oxygen [DO] measurements) were used to visualize whole‐river ecosystem functional responses to these wastewater treatment upgrades. There was a 60% reduction in ecosystem respiration during summer, in response to reductions in effluent total ammonia inputs, causing a shift from net heterotrophy to net autotrophy, and contraction of river metabolic fingerprints. This resulted in major improvements in summer DO concentrations, with reductions in the percentage of days during summer that DO minima fell below water‐quality guidelines for protection of aquatic early life stages, from 88% to ≤16%. The results also point to potential cascading impacts on coupled phosphorus and nitrogen cycles, which may generate further improvements in river water quality. During the summer, high rates of river metabolism and nutrient retention may result in measured water‐column nutrient concentrations potentially underestimating nutrient pressures. This study also demonstrates the value of combining river metabolism with nutrient monitoring for a more holistic understanding of the role of nutrients in river ecosystem health and function. River metabolism was used to explore aquatic ecosystem impacts of wastewater nitrification treatment.River metabolism was stimulated by effluent inputs but was also a driver of in‐river nutrient retention.Reduced effluent ammonia inputs resulted in contracted metabolic fingerprints and a shift from net heterotrophy to autotrophy.Instream nutrient retention may result in water‐column concentrations underestimating nutrient pressures.Demonstrates value of metabolism and nutrient monitoring for more holistic understanding of river ecosystem health.

Human inborn errors of thymic T cell tolerance underlie the production of autoantibodies (auto-Abs) neutralizing type I IFNs, which predispose to severe viral diseases. We analyze 131 female patients with X-linked dominant incontinentia pigmenti (IP), heterozygous for loss-of-function (LOF) NEMO variants, from 99 kindreds in 10 countries. Forty-seven of these patients (36%) have auto-Abs neutralizing IFN-α and/or IFN-ω, a proportion 23 times higher than that for age-matched female controls. This proportion remains stable from the age of 6 years onward. On imaging, female patients with IP have a small, abnormally structured thymus. Auto-Abs against type I IFNs confer a predisposition to life-threatening viral diseases. By contrast, patients with IP lacking auto-Abs against type I IFNs are at no particular risk of viral disease. These results suggest that IP accelerates thymic involution, thereby underlying the production of auto-Abs neutralizing type I IFNs in at least a third of female patients with IP, predisposing them to life-threatening viral diseases.

Immunotherapy-related adverse events (irAEs) associated with immune-checkpoint inhibitors can affect nearly any organ system including commonly the luminal gastrointestinal tract, hepatobiliary system, lungs, endocrine glands, and skin, many of which have described imaging manifestations. In patients without clinically suspected irAEs, imaging findings may be the first indication of an abnormality that prompts further workup to facilitate early detection and initiation of appropriate treatment, such as therapy discontinuation or corticosteroid therapy. While some irAEs have well described imaging correlates, such as pneumonitis, hypophysitis, and colitis, others are not well described, such as nephritis. We report 2 cases of irAE nephritis associated with PD-1 inhibitor therapy and their imaging features.

From 2014–2019, 8 juvenile black bears (Ursus americanus) from different geographic regions were presented to the California Department of Fish and Wildlife because of emaciation, alopecia, and exfoliative dermatitis that resulted in death or euthanasia. Autopsy and histopathology revealed that all 8 bears had generalized hyperkeratotic dermatitis, folliculitis, and furunculosis. Skin structures were heavily colonized by fungal hyphae and arthrospores; fungal cultures of skin from 7 bears yielded Trichophyton equinum, a zoophilic dermatophyte reported only rarely in non-equid species. Additional skin conditions included mites (5), ticks (2), and coagulase-negative Staphylococcussp. infections (2). No other causes of morbidity or mortality were identified. Molecular comparisons performed at the University of Texas Fungal Reference Laboratory determined that all isolates produced identical banding patterns, potentially representing a clonal population. Dermatophytosis is commonly localized and limited to the stratum corneum of the epidermis and hair follicles. Generalized disease with dermal involvement is rare in immunocompetent individuals; illness, malnutrition, age, or immunosuppression may increase susceptibility. Underlying causes for the severe disease impact in these bears were not evident after physical or postmortem examination. The mechanism by which bears from different geographic locations had severe, T. equinum–associated dermatophytosis from a potentially clonal dermatophyte could not be explained and warrants further investigation.

Background: After the reports of severe adverse reactions to the AstraZeneca ChAdOx1-S-nCoV-19 vaccine, patients who had received one dose of ChAdOx1-S-nCoV-19 vaccine were recommended a second dose of Pfizer’s BNT162b2 vaccine. In hemodialysis patients, we compared the humoral immunogenicity and tolerability of homologous vaccination with ChAdOx1-nCoV-19/ChAdOx1-nCoV-19 (ChAd/ChAd) and BNT162b2/BNT162b2 (BNT/BNT) with heterologous vaccination of first dose of ChAdOx1-nCoV-19 and a second dose with BNT162b2 (ChAd/BNT). Methods: In a multicenter prospective observational study, SARS-CoV-2 spike-IgG antibody levels, Nucleocapsid-protein-IgG-antibodies, and vaccine tolerability were assessed 6 weeks after second SARS-CoV-2 vaccination in 137 hemodialysis patients and 24 immunocompetent medical personnel. Results: In COVID-19-naïve hemodialysis patients, significantly higher median SARS-CoV-2-spike IgG levels were found after ChAd/BNT (N = 16) compared to BNT/BNT (N = 100) or ChAd/ChAd (N = 10) (1744 [25th–75th percentile 276–2840] BAU/mL versus 361 [25th–75th percentile 120–936] BAU/mL; p = 0.009; 1744 [25th–75th percentile 276–2840] BAU/mL versus 100 [25th–75th percentile 41–346] BAU/mL; p = 0.017, respectively). Vaccinated, COVID-19-naïve medical personnel had median SARS-CoV-2 spike-IgG levels of 650 (25th–75th percentile 217–1402) BAU/mL and vaccinated hemodialysis patients with prior COVID-19 7047 (25th–75th percentile 685–10,794) BAU/mL (N = 11). In multivariable regression analysis, heterologous vaccination (ChAd/BNT) of COVID-19-naïve hemodialysis patients was independently associated with SARS-CoV-2 spike-IgG levels. The first dose of ChAd and the second dose of BNT after the first vaccination with ChAd (heterologous vaccination, ChAd/BNT) were associated with more frequent but manageable side effects compared with homologous BNT. Conclusions: Within the limitations of this study, heterologous vaccination with ChAd/BNT appears to induce stronger humoral immunity and more frequent but manageable side effects than homologous vaccination with BNT/BNT or with ChAd/ChAd in COVID-19-naïve hemodialysis patients. Graphical abstract:

Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system. B lymphocytes in the cerebrospinal fluid (CSF) of patients with MS contribute to inflammation and secrete oligoclonal immunoglobulins1,2. Epstein–Barr virus (EBV) infection has been epidemiologically linked to MS, but its pathological role remains unclear3. Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM) and provide structural and in vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements and the crystal structure of the EBNA1–peptide epitope in complex with the autoreactive Fab fragment enabled tracking of the development of the naive EBNA1-restricted antibody to a mature EBNA1–GlialCAM cross-reactive antibody. Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates disease in a mouse model of MS, and anti-EBNA1 and anti-GlialCAM antibodies are prevalent in patients with MS. Our results provide a mechanistic link for the association between MS and EBV and could guide the development of new MS therapies.

The mutualistic relationship of gut-resident microbiota and the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a largely non-aggressive immune cell compartment1,2. The consequences of disturbing this balance include proximal inflammatory conditions, such as Crohn’s disease, and systemic illnesses. This equilibrium is achieved in part through the induction of both effector and suppressor arms of the adaptive immune system. Helicobacterspecies induce T regulatory (Treg) and T follicular helper (TFH) cells under homeostatic conditions, but induce inflammatory T helper 17 (TH17) cells when induced Treg(iTreg) cells are compromised3,4. How Helicobacterand other gut bacteria direct T cells to adopt distinct functions remains poorly understood. Here we investigated the cells and molecular components required for iTregcell differentiation. We found that antigen presentation by cells expressing RORγt, rather than by classical dendritic cells, was required and sufficient for induction of Tregcells. These RORγt+cells—probably type 3 innate lymphoid cells and/or Janus cells5—require the antigen-presentation machinery, the chemokine receptor CCR7 and the TGFβ activator αvintegrin. In the absence of any of these factors, there was expansion of pathogenic TH17 cells instead of iTregcells, induced by CCR7-independent antigen-presenting cells. Thus, intestinal commensal microbes and their products target multiple antigen-presenting cells with pre-determined features suited to directing appropriate T cell differentiation programmes, rather than a common antigen-presenting cell that they endow with appropriate functions.