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A major complication of primary Sjögren's syndrome (pSS) is development of mucosa associated lymphoid tissue (MALT) B-cell lymphoma, particularly in salivary glands. These lymphomas express FcRL4 and are characteristically associated with lymphoepithelial lesions. Neoplastic B-cells may be derived from non-neoplastic glandular intraductal B-cells, also virtually all expressing FcRL4. A characteristic feature of MALT lymphomas is the production of rheumatoid factors (RFs), which are largely encoded by stereotypic immunoglobulin variable heavy chain (IGHV) sequences. The aim of this study was to examine whether there is a relationship between the intraductal and periductal B-cells and whether the intraductal B-cells are selected for RF. RNA was extracted from laser-microdissected infiltrated ductal areas and periductal infiltrates from frozen parotid gland tissue sections of 5 pSS patients. PCR amplified IGHV transcripts were cloned into pCR™4-TOPO vector and subsequently sequenced. Microdissected ducts yielded 96 unique IGHV sequences derived from intraductal B-cells, while 119 unique IGHV sequences were obtained from periductal infiltrates. No major difference in VH-gene usage was observed between intraductal and periductal B-cells. Nearly all (>90%) IGHV sequences derived from both intraductal and periductal B-cells were mutated. Clonal expansions as defined by shared VDJ rearrangements were also present among both intraductal and periductal B-cells: in total 32 clones were found, from which 12 were located within ducts, 15 in periductal areas, and five clones shared members in both areas. We observed 12 IGHV rearrangements encoding for RF sequences from which two were derived from intraductal B-cells and 10 from periductal B-cells. Nine RF sequences were part of a clone. Together these findings indicate that intraductal and periductal B-cells are closely related to each other. Intraductal B-cells are most likely derived from periductal B-cells. We did not obtain evidence that RF-specific B-cells are enriched within the striated ducts. We speculate that in principle any activated B-cell can enter the striated ducts from the periductal infiltrate, irrespective of its antigenic specificity. Within the ducts, these B-cells may receive additional activation and proliferation signals, to further expand at these sites and by acquisition of driver-mutations develop toward lymphoma.

Climate change represents a major threat to lotic freshwater ecosystems and their ability to support the provision of ecosystem services. England’s chalk streams are in a poor state of health, with significant concerns regarding their resilience, the ability to adapt, under a changing climate. This paper aims to quantify the effect of climate change on hydroecological response for the River Nar, south-east England. To this end, we apply a coupled hydrological and hydroecological modelling framework, with the UK probabilistic climate projections 2009 (UKCP09) weather generator serving as input (CMIP3 A1B high emissions scenario, 2021 to the end-of-century). The results indicate a minimal change in the long-term mean hydroecological response over this period. In terms of interannual variability, the median hydroecological response is subject to increased uncertainty, whilst lower probability extremes are virtually certain to become more homogeneous (assuming a high emissions scenario). A functional matrix, relating species-level macroinvertebrate functional flow preferences to functional food groups reveals that, on the baseline, under extreme conditions, key groups are underrepresented. To date, despite this limited range, the River Nar has been able to adapt to extreme events due to interannual variation. In the future, this variation is greatly reduced, raising real concerns over the resilience of the river ecosystem, and chalk ecosystems more generally, under climate change.

Previous studies in rodents have indicated that only a minor fraction of the immunoglobulin heavy chain variable region (IGHV-Cμ) transcripts carry somatic mutations and are considered memory B cells. This is in marked contrast to humans where nearly all marginal zone B (MZ-B) cells are mutated. Here we show in rats that the proportion of mutated IgM+ MZ-B cells varies significantly between the various IGHV genes analyzed, ranging from 27% mutated IGHV5 transcripts to 65% mutated IGHV4 transcripts. The observed data on mutated sequences in clonally-related B cells with a MZ-B cell or follicular B (FO-B) cell phenotype indicates that mutated IgM+ MZ-B and FO-B cells have a common origin. To further investigate the origin of mutated IgM+ MZ-B cells we determined whether mutations occurred in rearranged IGHV-Cμ transcripts using IGHV4 and IGHV5 genes from neonatal rat MZ-B cells and FO-B cells. We were not able to detect mutations in any of the IGHV4 and IGHV5 genes expressed by MZ-B cells or FO-B cells obtained from neonatal rat spleens. Germinal centres (GCs) are absent from neonatal rat spleen in the first few weeks of their life, and no mutations were found in any of the neonatal sequences, not even in the IGHV4 gene family which accumulates the highest number of mutated sequences (66%) in the adult rat. Therefore, these data do not support the notion that MZ-B cells in rats mutate their IGHV genes as part of their developmental program, but are consistent with the notion that mutated rat MZ-B cells require GCs for their generation. Our findings support that the splenic MZ of rats harbors a significant number of memory type IgM+ MZ-B cells with mutated IGHV genes and propose that these memory MZ-B cells are probably generated as a result of an antigen driven immune response in GCs, which still remains to be proven.

River systems provide diverse ecosystem services (ES), such as flood regulation (regulating), fresh water (provisioning), nutrient cycling (supporting), and recreation (cultural), among others. The construction of infrastructure (e.g., for hydropower, irrigation) enhances the delivery of tangible ES for example food or energy (generally provisioning) to meet human needs. However, the resulting change to river flows threatens both the ecological health of a river and its ability to provide intangible but vital ES, for example those which support the delivery of other services. Understanding these supporting ES processes in river systems is essential to fully recognise the impact of water resources development on ES delivery. Whilst approaches for assessing instream supporting ES are under development, to date few provide quantitative methods for assessing delivery. Thus, this paper sets out a framework for the assessment of instream supporting ES using hydroecological modelling. It links supporting ES delivery to fluvial hydrological indicators through the use of ecologically relevant hydrological indices and macroinvertebrate flow preferences. The proposed framework is demonstrated on the Beas River basin (Western Himalayas, India), and is flexible enough to be transferred to a basin-wide model, thereby allowing ES relationships to be accounted for in basin-wide water resources planning.

In this paper, we explore how we can use catchment resilience as a unifying concept to manage and regulate catchments, using structured reviews to support our perspective. Catchments are complex systems with interrelated natural, social, and technical aspects. The exposure, vulnerability, and resilience of these aspects (separately and in combination) are the latent conditions, which, when triggered by a hydrohazard, result in catchment impacts. In complex catchment systems, resilience is the ability to bounce back, the ability to absorb, and the ability to transform. When all three abilities are accounted for, we are forced to consider the interactions of the catchment system. Six main complexity concepts can be used to frame how we approach evaluating catchment resilience. These concepts are: natural-social-technical aspects, interactions, spatial scales, time scales, multiple forms of evidence, and uncertainty. In analysing these complexity concepts, we have found that there are several gaps in current practice. Requirements for future methodological approaches are suggested. Central to any effective approach is the incorporation of a linking systems or interaction analysis, which draws together the natural-social-technical system in a meaningful way. If our approaches do not begin to acknowledge the interdependencies and interactions, we may miss substantial opportunities to enhance catchment resilience.

Previous studies revealed high incidence of acquired N-glycosylation sites acquired N-glycosylation sites in RNA transcripts encoding immunoglobulin heavy variable region (IGHV) 3 genes from parotid glands of primary Sjögren's syndrome (pSS) patients. In this study, next generation sequencing was used to study the extent of ac-Nglycs among clonally expanded cells from all IGVH families in the salivary glands of pSS patients. RNA was isolated from parotid gland biopsies of five pSS patients and five non-pSS sicca controls. IGHV sequences covering all functional IGHV genes were amplified, sequenced, and analyzed. Each biopsy recovered 1,800-4,000 unique IGHV sequences. No difference in IGHV gene usage was observed between pSS and non-pSS sequences. Clonally related sequences with more than 0.3% of the total number of sequences per patient were referred to as dominant clone. Overall, 70 dominant clones were found in pSS biopsies, compared to 15 in non-pSS. No difference in percentage mutation in dominant clone-derived IGHV sequences was seen between pSS and non-pSS. In pSS, no evidence for antigen-driven selection in dominant clones was found. We observed a significantly higher amount of ac-Nglycs among pSS dominant clone-derived sequences compared to non-pSS. Ac-Nglycs were, however, not restricted to dominant clones or IGHV gene. Most ac-Nglycs were detected in the framework 3 region. No stereotypic rheumatoid factor rearrangements were found in dominant clones. Lineage tree analysis showed in four pSS patients, but not in non-pSS, the presence of the germline sequence from a dominant clone. Presence of germline sequence and mutated IGHV sequences in the same dominant clone provide evidence that this clone originated from a naïve B-cell recruited into the parotid gland to expand and differentiate locally into plasma cells. The increased presence of ac-Nglycs in IGHV sequences, due to somatic hypermutation, might provide B-cells an escape mechanism to survive during immune response. We speculate that glycosylation of the B-cell receptor makes the cell sensitive to environmental lectin signals to contribute to aberrant B-cell selection in pSS parotid glands.

ObjectivesTo evaluate humoral and cellular immune responses and adverse events (AEs) after COVID-19 vaccination in patients with primary Sjögren’s syndrome (pSS) compared to healthy controls (HC), and disease activity following vaccination in patients with pSS.Methods67 patients with pSS and 33 HC (ratio 2:1) received COVID-19 vaccinations following the Dutch vaccination programme. Patients with pSS did not use immunomodulatory drugs, except hydroxychloroquine. Anti-spike 1 receptor binding domain IgG serum antibody levels were measured 28 days after complete vaccination. AEs were collected 7 days after vaccination. In a subgroup, salivary anti-SARS-CoV-2 antibodies and T-cell response by interferon-γ enzyme-linked immune absorbent spot was measured.Results47 patients with pSS (70%) and 14 HC (42%) received BNT162b2 (Pfizer-BioNtech), 13 (19%) and 5 (15%) received ChAdOx1 nCoV-19 (AstraZeneca), 6 (9%) and 8 (24%) received mRNA-1273 (Moderna), and 1 (1%) and 6 (18%) received Ad.26.COV2.S (Janssen). All participants had positive anti-SARS-CoV-2 antibody levels (>2500 AU/mL) postvaccination. No differences in anti-SARS-CoV-2 antibody levels were observed between patients with pSS and HC, for each vaccine type. Salivary anti-SARS-CoV-2 IgG antibodies also increased, and a T-cell response was observed in patients with pSS and HC. Frequencies of systemic AEs were comparable between patients with pSS and HC (first vaccination: 34/67 (51%) vs 16/33 (48%), p=0.83; second: 41/66 (62%) vs 14/25 (56%), p=0.59). No significant worsening was observed in patient-reported and systemic disease activity, including auto-antibodies.ConclusionsPatients with pSS had similar humoral and cellular immune responses as HC, suggesting COVID-19 vaccination is effective in patients with pSS. AEs were also comparable, and no increase in disease activity was seen in patients with pSS.

The COVID-19 pandemic has impacted public health, the economy and society—both directly and indirectly. Few approaches exist to understand these complex impacts in a way that (1) acknowledges cross-sectoral interdependencies; (2) models how short-term shocks translate into impacts on longer-term outcomes; (3) builds in local, contextual variation; and (4) recognises a wide set of priorities. The Urban Systems Abstraction Hierarchy (USAH) is proposed as an approach with these capabilities, and applied to Edinburgh (UK) between March-October 2020 to identify city-level impacts of the pandemic and associated policy responses. Results show changing priorities in the system and suggest areas which should be targeted for future urban resilience planning in Edinburgh for both short-term shocks and long-term recovery. This makes both methodological contributions (in the form of testing a new complex systems approach) and practical contributions (in the form of city-specific results which inform different aspects of resilience) to urban science.

With evidence suggesting that climate change is resulting in changes within the hydrologic cycle, the ability to robustly model hydroclimatic response is critical. This paper assesses how extreme runoff—1:2- and 1:30-year return period (RP) events—may change at a regional level across the UK by the 2080s (2069–2098). Capturing uncertainty in the hydroclimatic modelling chain, flow projections were extracted from the EDgE (End-to-end Demonstrator for improved decision-making in the water sector in Europe) multi-model ensemble: five Coupled Model Intercomparison Project (CMIP5) General Circulation Models and four hydrological models forced under emissions scenarios Representative Concentration Pathway (RCP) 2.6 and RCP 8.5 (5 × 4 × 2 chains). Uncertainty in extreme value parameterisation was captured through consideration of two methods: generalised extreme value (GEV) and generalised logistic (GL). The method was applied across 192 catchments and aggregated to eight regions. The results suggest that, by the 2080s, many regions could experience large increases in extreme runoff, with a maximum mean change signal of +34% exhibited in East Scotland (1:2-year RP). Combined with increasing urbanisation, these estimates paint a concerning picture for the future UK flood landscape. Model chain uncertainty was found to increase by the 2080s, though extreme value (EV) parameter uncertainty becomes dominant at the 1:30-year RP (exceeding 60% in some regions), highlighting the importance of capturing both the associated EV parameter and ensemble uncertainty.

We have mapped and annotated the variable region of the immunoglobulin heavy (IGH) gene locus of the Brown Norway (BN) rat (assembly V3.4; Rat Genomic Sequence Consortium). In addition to known variable region genes, we found 12 novel previously unidentified functional IGHV genes and 1 novel functional IGHD gene. In total, the variable region of the rat IGH locus is composed of at least 353 unique IGHV genes, 21 IGHD genes, and 5 IGHJ genes, of which 131, 14, and 4 are potentially functional genes, respectively. Of all species studied so far, the rat seems to have the highest number of functional IGHV genes in the genome. Rat IGHV genes can be classified into 13 IGHV families based on nucleotide sequence identity. The variable region of the BN rat spans a total length of approximately 4.9 Mb and is organized in a typical translocon organization. Like the mouse, members of the various IGHV gene families are more or less grouped together on the genome, albeit some members of IGHV gene families are found intermingled with each other. In the rat, the largest IGHV gene families are IGHV1, IGHV2, and IGHV5. The overall conclusion is that the genomic organization of the variable region of the rat IGH locus is strikingly similar to that of the mouse, illustrating the close evolutionary relationship between these two species.