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This study surveyed the members of a professional library organization for their perceptions of their online librarianship role. In particular, the survey sought to examine any change in online librarianship roles after March 2020 as a result of the COVID-19 pandemic lockdowns. Participants were administered a survey comprised of both quantitative and qualitative response options. Findings present a nuanced professional environment post-lockdown in which individual job duties largely remained the same; however participants reported increased demands stemming from workplace issues, including attrition and lack of resources.

The mid-17th century is characterized by a cluster of explosive volcanic eruptions in the 1630s and 1640s, deteriorating climatic conditions culminating in the Maunder Minimum as well as political instability and famine in regions of Western and Northern Europe as well as China and Japan. This contribution investigates the sources of the eruptions of the 1630s and 1640s and their possible impact on contemporary climate using ice-core, tree-ring and historical evidence, but will also look into the socio-political context in which they occurred and the human responses they may have triggered. Three distinct sulfur peaks are found in the Greenland ice core record in 1637, 1641–42 and 1646. In Antarctica, only one unambiguous sulfate spike is recorded, peaking in 1642. The resulting bipolar sulfur peak in 1641–1642 can likely be ascribed to the eruption of Mount Parker (6° N, Philippines) on December 26, 1640, but sulfate emitted from Koma-ga-take (42° N, Japan) volcano on July 31, 1641, has potentially also contributed to the sulphate concentrations observed in Greenland at this time. The smaller peaks in 1637 and 1646 can be potentially attributed to the eruptions of Hekla (63° N, Iceland) and Shiveluch (56° N, Russia), respectively. To date, however, none of the candidate volcanoes for the mid-17th century sulphate peaks have been confirmed with tephra preserved in ice cores. Tree-ring and written sources point to severe and cold conditions in the late 1630s and early 1640s in various parts of Europe, and to poor harvests. Yet the early 17th century was also characterized by widespread warfare across Europe – and in particular the Thirty Years’ War (1618–1648), rendering any attribution of socio-economic crisis to volcanism challenging. In China and Japan, historical sources point to extreme droughts and famines starting in the late 1630s, and thus preceding the eruptions by some years. The case of the eruption cluster in the late 1630s and early 1640s and the climatic and societal conditions recorded in its aftermath thus offer a textbook example of difficulties in (i) unambiguously distinguishing volcanically induced cooling, wetting or drying from natural climate variability, and (ii) attributing political instability, harvest failure and famines solely to volcanic climatic impacts. This example shows that the impacts of past volcanism must always be studied within the contemporary socio-economic contexts, but that it is also time to most past reductive framings and sometimes reactionary oppositional stances in which climate (and environment more broadly) either is or is not deemed an important contributor to major historical events.

Paediatric-type diffuse high-grade gliomas are classified into distinct subgroups based upon their location and defining molecular alterations, with very poor clinical outcomes in patients >3yrs. This extensive inter-tumour heterogeneity is further complicated by a wide diversity of genotypically- and phenotypically-distinct subclonal populations within individual tumours, providing a substantial barrier to developing effective treatments. We have sought to understand the dynamic cellular make-up of PDHGGs such that novel strategies aimed at targeting specific subpopulations based upon their contribution to disease progression as whole may be employed. Two complementary approaches have been undertaken to address this – first by carrying out single-cell profiling of bulk specimens, and the second isolation and propagation of single-cell-derived stem cell-like cultures in vitro. To-date we have studied 10 cases and a total of 218 subclonal colonies from both DMG-H3K27 and DHG-WT. In a spinal metastatic case of DMG-H3K27, lpWGS-FISH highlighted subpopulations driven by mis-segregation of amplified oncogenic ecDNA, and mutually exclusive subpopulations defined by MYCN, PDGFRA and CCND1. Through integrated analysis of scRNA-seq and scATAC-seq, we show distinct chromatin accessibility profiles to underlie gene expression signatures defining unique subpopulations of cells. In addition to cycling populations and those associated with lineage-specificity, we identified ‘aggressive’ subpopulations defined by significant upregulation of immediate early response genes such as FOS/FOSL1/JUN, those associated with promotion of invasion-migration such as SERPINs and MMPs. These subpopulations could be mapped to isolated single-cell-derived subclones with highly proliferative or motile phenotypes, defined by comprehensive profiling of expressed and secreted proteins. Differential cis-regulation driving cell identity-tumorigenesis was found in one example to occur via a trans-histone mechanism mediated by an H4-lysine-methyltransferase, KMT5B. Application of functionally-defined interventional strategies aimed at disrupting the interactions between these subpopulations based upon evolutionary biology principles may offer a novel approach to treat these otherwise incurable tumours in children and young adults.

BACKGROUND: Gliomatosis cerebri (GC), a radiologically defined diffusely infiltrating glioma, is no longer considered a distinct entity since the 2016 WHO classification for tumors of the CNS. Due to its rarity and dismal prognosis treatment recommendations in children remain ambiguous. Using central neuroradiological review, we performed a multi-institutional, retrospective study of GC providing comprehensive radiological, clinical, and (epi)genetic characterization. RESULTS: We included 104 patients between 1-19 years. Within a median follow-up of 15.5 months (range, 2.3-138.8), 93 patients (89.4 %) had died, 4 (3.8 %) were lost to follow-up and 7 (6.8 %) were alive with stable/progressive disease. Median progression-free- (PFS) and overall survival (OS) were 8.6 months (interquartile range, 4.3-14.0) and 15.5 months (10.9-27.7), respectively. Former WHO grading correlated significantly with median OS: WHO °II: 47.8 months (25.2-55.7); WHO °III: 15.9 months (11.4-26.3); WHO °IV: 10.4 months (8.8-14.4) (p

Historical precipitation records are fundamental for the management of water resources, yet rainfall observations typically span 100–150 years at most, with considerable uncertainties surrounding earlier records. Here, we analyse some of the longest available precipitation records globally, for England and Wales, Scotland and Ireland. To assess the credibility of these records and extend them further back in time, we statistically reconstruct (using independent predictors) monthly precipitation series representing these regions for the period 1748–2000. By applying the Standardized Precipitation Index at 12‐month accumulations (SPI‐12) to the observed and our reconstructed series we re‐evaluate historical meteorological droughts. We find strong agreement between observed and reconstructed drought chronologies in post‐1870 records, but divergence in earlier series due to biases in early precipitation observations. Hence, the 1800s decade was less drought prone in our reconstructions relative to observations. Overall, the drought of 1834–1836 was the most intense SPI‐12 event in our reconstruction for England and Wales. Newspaper accounts and documentary sources confirm the extent of impacts across England in particular. We also identify a major, “forgotten” drought in 1765–1768 that affected the British‐Irish Isles. This was the most intense event in our reconstructions for Ireland and Scotland, and ranks first for accumulated deficits across all three regional series. Moreover, the 1765–1768 event was also the most extreme multi‐year drought across all regional series when considering 36‐month accumulations (SPI‐36). Newspaper and other sources confirm the occurrence and major socio‐economic impact of this drought, such as major rivers like the Shannon being fordable by foot. Our results provide new insights into historical droughts across the British Irish Isles. Given the importance of historical droughts for stress‐testing the resilience of water resources, drought plans and supply systems, the forgotten drought of 1765–1768 offers perhaps the most extreme benchmark scenario in more than 250‐years., We reconstruct and re‐evaluate historical droughts across the British Irish Isles (England and Wales, Scotland and Ireland) since 1748 and identify a major, “forgotten” drought in 1765–1768. We show that the event was likely the most extreme multi‐year drought across the region. Newspaper and other sources confirm the occurrence and major socio‐economic impact of this drought, which offers perhaps the most extreme benchmark scenario in more than 250‐years for stress‐testing drought and water resource plans.

Frontotemporal lobar degeneration (FTLD) consists of a clinically, pathologically and genetically heterogeneous group of neurodegenerative disorders that chiefly affect frontal and temporal lobes. Clinical presentation in FTLD includes behavioural variant frontotemporal dementia, progressive nonfluent aphasia and semantic dementia (SD). Pathologically, FTLD is subdivided based on accumulation of abnormal intracellular proteins including transactivation response DNA-binding protein 43 kDa (TDP-43) [1, 2]. TDP-43 pathology in FTLD is classified into five pathological subgroups depending on its morphological features: TDP-43 type A, B, C, D and E [2, 3].

Paediatric-type diffuse high-grade gliomas are classified into distinct subgroups based upon their location and defining molecular alterations, with very poor clinical outcomes in patients >3yrs. This extensive inter-tumour heterogeneity is further complicated by a wide diversity of genotypically- and phenotypically-distinct subclonal populations within individual tumours, providing a substantial barrier to developing effective treatments. We aimed to understand the dynamic cellular make-up of PDHGGs such that novel strategies aimed at targeting specific subpopulations based upon their contribution to disease progression as whole may be employed. Two complementary approaches have been undertaken to address this – first by carrying out single-cell profiling of bulk specimens, and the second isolation and propagation of single-cell-derived stem cell-like cultures in vitro. To-date we have studied 10 cases and a total of 218 subclonal colonies from both DMG-H3K27 and DHG-WT. In a spinal metastatic case of DMG-H3K27, lpWGS/FISH highlighted subpopulations driven by mis-segregation of amplified oncogenic ecDNA, and mutually exclusive subpopulations defined by MYCN, PDGFRA and CCND1. Through integrated analysis of scRNA-seq and scATAC-seq, we show distinct chromatin accessibility profiles to underlie gene expression signatures defining unique subpopulations of cells. In addition to cycling populations and those associated with lineage-specificity, we identified ‘aggressive’ subpopulations defined by significant upregulation of immediate early response genes such as FOS/FOSL1/JUN, those associated with promotion of invasion/migration such as SERPINs and MMPs. These subpopulations could be mapped to isolated single-cell-derived subclones with highly proliferative and/or motile phenotypes, defined by comprehensive profiling of expressed and secreted proteins. Differential cis-regulation driving cell identity/tumorigenesis was found in one example to occur via a trans-histone mechanism mediated by an H4-lysine-methyltransferase, KMT5B. Application of functionally-defined interventional strategies aimed at disrupting the interactions between these subpopulations based upon evolutionary biology principles may offer a novel approach to treat these otherwise incurable tumours in children and young adults.

PDHGG are a diverse group of childhood brain tumours comprising multiple subgroups carrying distinct molecular drivers. Patient-derived models accurately recapitulating this underlying biology are critical for mechanistic/preclinical studies aimed at improving patient outcome, however their behaviour over time in the environments in which they are propagated, and how this relates to the human disease, is largely unknown. To explore this, we collected 94 models of PDHGG established as 2D/3D stem cell cultures in vitro, and generated patient-derived xenografts (PDX) in 33/62 specimens implanted orthotopically in vivo. We carried out exome/targeted sequencing, methylation profiling and RNAseq to profile cells through their first 25 passages in culture, and sequential implantation from p0-p2 in mice. In 15/83 cultures, we observed enrichment of gene expression signatures of non-malignant cells over the first 5 passages, with concurrent depletion of somatic mutations/CNAs, excluding them from further study. Validated models retained tumour-matched genotypes, CNAs and driver alterations including H3.3G34R, H3.3/H3.1K27M, BRAF and ACVR1 over time, however subclonal alterations underwent selection in culture which profoundly altered their response to targeted drug treatment. In 6/7 PDGFRA-mutant models, activating mutations were selected against between p5-20 in 2D and/or 3D, whilst MAPK pathway mutations in NF1/PIK3R1 similarly diverged over 15 passages under different growth conditions, resulting in isogenic models with differential signalling, in vivo tumorigenicity, and in vitro sensitivity to multiple MEK inhibitors. In PDXs, serial xenografting reduced the time to tumour formation by up to half, with a concomitant shift in clonal architecture. Multi-region sequencing of diffusely-infiltrating tumours showed selection for alterations such as PIK3CA/NF1 at distant sites, with evidence for convergent evolution of subclonal mutations, as in human tumours. Understanding the evolutionary dynamics of targetable/predictive alterations in PDHGG model systems is key to developing new and effective therapeutic interventions in this highly heterogenous disease.

We present an overview of a weather diary for Glendooen, Co. Donegal in Ireland for the years 1846–1875. The record contains valuable direct observations of temperature and precipitation for the years 1864–1871, together with qualitative descriptions of weather covering the years of the Great Irish Famine and the exceptionally wet year of 1872.

Large-scale 3D histology reconstruction of the human brain with MRI as volumetric reference generally requires reassembling the tissue blocks into the MRI space, prior to any further reconstruction of the histology of the individual blocks. This is a challenging registration problem, particularly in the frequent case that blockface photographs of paraffin embedded tissue are used as intermediate modality, as their contrast between white and gray matter is rather low. Here we propose a registration framework to address this problem, relying on two key components. First, blocks are simultaneously aligned to the MRI while exploiting the spatial constraints that they impose on each other, by means of a customized soft shape constraint (similarly to a jigsaw puzzle). And second, we adopt a hierarchical optimization strategy that capitalizes on our prior knowledge on the slicing and blocking procedure. Our framework is validated quantitatively on synthetic data, and qualitatively on the histology of a whole human hemisphere.