Virological characterization of the 2022 outbreak-causing monkeypox virus using human keratinocytes and colon organoids

ヒトiPS細胞由来大腸オルガノイドおよびヒトケラチノサイトを用いたmpoxウイルス2022年株の解析. 京都大学プレスリリース. 2023-06-07.The outbreak-causing monkeypox virus of 2022 (2022 MPXV) is classified as a clade IIb strain and phylogenetically distinct from prior endemic MPXV strains (clades I or IIa), suggesting that its virological properties may also differ. Here, we used human keratinocytes and induced pluripotent stem cell-derived colon organoids to examine the efficiency of viral growth in these cells and the MPXV infection-mediated host responses. MPXV replication was much more productive in keratinocytes than in colon organoids. We observed that MPXV infections, regardless of strain, caused cellular dysfunction and mitochondrial damage in keratinocytes. Notably, a significant increase in the expression of hypoxia-related genes was observed specifically in 2022 MPXV-infected keratinocytes. Our comparison of virological features between 2022 MPXV and prior endemic MPXV strains revealed signaling pathways potentially involved with the cellular damages caused by MPXV infections and highlights host vulnerabilities that could be utilized as protective therapeutic strategies against human mpox in the future

Classifying the unclassifiable – A Delphi study to reach consensus on the fibrotic nature of diseases

Background Traditionally, clinical research has focused on individual fibrotic diseases or fibrosis in a particular organ. However, it is possible for people to have multiple fibrotic diseases. While multi-organ fibrosis may suggest shared pathogenic mechanisms, yet there is no consensus on what constitutes a fibrotic disease and therefore fibrotic multimorbidity. Aim A Delphi study was performed to reach consensus on which diseases may be described as fibrotic. Methods Participants were asked to rate a list of diseases, sub-grouped according to eight body regions, as ‘fibrotic manifestation always present’, ‘can develop fibrotic manifestations’, ‘associated with fibrotic manifestations’ or ‘not fibrotic nor associated’. Classifications of ‘fibrotic manifestation always present’ and ‘can develop fibrotic manifestations’ were merged and termed ‘fibrotic’. Clinical consensus was defined according to the interquartile range, having met a minimum number of responses. Clinical agreement was used for classification where diseases did not meet the minimum number of responses (required for consensus measure), were only classified if there was 100% consensus on disease classification. Results After consulting experts, searching the literature and coding dictionaries, a total of 323 non-overlapping diseases which might be considered fibrotic were identified; 92 clinical specialists responded to the first round of the survey. Over three survey rounds, 240 diseases were categorized as fibrotic via clinical consensus and 25 additional diseases through clinical agreement. Conclusion Using a robust methodology, an extensive list of diseases was classified. The findings lay the foundations for studies estimating the burden of fibrotic multimorbidity, as well as investigating shared mechanisms and therapies

RAS oncogenic activity predicts response to chemotherapy and outcome in lung adenocarcinoma.

Activating mutations in KRAS occur in 32% of lung adenocarcinomas (LUAD). Despite leading to aggressive disease and resistance to therapy in preclinical studies, the KRAS mutation does not predict patient outcome or response to treatment, presumably due to additional events modulating RAS pathways. To obtain a broader measure of RAS pathway activation, we developed RAS84, a transcriptional signature optimised to capture RAS oncogenic activity in LUAD. We report evidence of RAS pathway oncogenic activation in 84% of LUAD, including 65% KRAS wild-type tumours, falling into four groups characterised by coincident alteration of STK11/LKB1, TP53 or CDKN2A, suggesting that the classifications developed when considering only KRAS mutant tumours have significance in a broader cohort of patients. Critically, high RAS activity patient groups show adverse clinical outcome and reduced response to chemotherapy. Patient stratification using oncogenic RAS transcriptional activity instead of genetic alterations could ultimately assist in clinical decision-making

Allele-specific miRNA-binding analysis identifies candidate target genes for breast cancer risk

Most breast cancer (BC) risk-associated single-nucleotide polymorphisms (raSNPs) identified in genome-wide association studies (GWAS) are believed to cis-regulate the expression of genes. We hypothesise that cis-regulatory variants contributing to disease risk may be affecting microRNA (miRNA) genes and/or miRNA binding. To test this, we adapted two miRNA-binding prediction algorithms-TargetScan and miRanda-to perform allele-specific queries, and integrated differential allelic expression (DAE) and expression quantitative trait loci (eQTL) data, to query 150 genome-wide significant ( P≤5×10-8 ) raSNPs, plus proxies. We found that no raSNP mapped to a miRNA gene, suggesting that altered miRNA targeting is an unlikely mechanism involved in BC risk. Also, 11.5% (6 out of 52) raSNPs located in 3'-untranslated regions of putative miRNA target genes were predicted to alter miRNA::mRNA (messenger RNA) pair binding stability in five candidate target genes. Of these, we propose RNF115, at locus 1q21.1, as a strong novel target gene associated with BC risk, and reinforce the role of miRNA-mediated cis-regulation at locus 19p13.11. We believe that integrating allele-specific querying in miRNA-binding prediction, and data supporting cis-regulation of expression, improves the identification of candidate target genes in BC risk, as well as in other common cancers and complex diseases.Funding Agency Portuguese Foundation for Science and Technology CRESC ALGARVE 2020 European Union (EU) 303745 Maratona da Saude Award DL 57/2016/CP1361/CT0042 SFRH/BPD/99502/2014 CBMR-UID/BIM/04773/2013 POCI-01-0145-FEDER-022184info:eu-repo/semantics/publishedVersio

Transcriptome pathways unique to dehydration tolerant relatives of modern wheat

Among abiotic stressors, drought is a major factor responsible for dramatic yield loss in agriculture. In order to reveal differences in global expression profiles of drought tolerant and sensitive wild emmer wheat genotypes, a previously deployed shock-like dehydration process was utilized to compare transcriptomes at two time points in root and leaf tissues using the Affymetrix GeneChip(R) Wheat Genome Array hybridization. The comparison of transcriptomes reveal several unique genes or expression patterns such as differential usage of IP(3)-dependent signal transduction pathways, ethylene- and abscisic acid (ABA)-dependent signaling, and preferential or faster induction of ABA-dependent transcription factors by the tolerant genotype that distinguish contrasting genotypes indicative of distinctive stress response pathways. The data also show that wild emmer wheat is capable of engaging known drought stress responsive mechanisms. The global comparison of transcriptomes in the absence of and after dehydration underlined the gene networks especially in root tissues that may have been lost in the selection processes generating modern bread wheats

Reconstructing El Niño Southern Oscillation using data from ships' logbooks, 1815- 1854. Part I: Methodology and Evaluation

The meteorological information found within ships’ logbooks is a unique and fascinating source of data for historical climatology. This study uses wind observations from logbooks covering the period 1815 to 1854 to reconstruct an index of El Niño Southern Oscillation (ENSO) for boreal winter (DJF). Statistically-based reconstructions of the Southern Oscillation Index (SOI) are obtained using two methods: principal component regression (PCR) and composite-plus-scale (CPS). Calibration and validation are carried out over the modern period 1979–2014, assessing the relationship between re-gridded seasonal ERA-Interim reanalysis wind data and the instrumental SOI. The reconstruction skill of both the PCR and CPS methods is found to be high with reduction of error skill scores of 0.80 and 0.75, respectively. The relationships derived during the fitting period are then applied to the logbook wind data to reconstruct the historical SOI. We develop a new method to assess the sensitivity of the reconstructions to using a limited number of observations per season and find that the CPS method performs better than PCR with a limited number of observations. A difference in the distribution of wind force terms used by British and Dutch ships is found, and its impact on the reconstruction assessed. The logbook reconstructions agree well with a previous SOI reconstructed from Jakarta rain day counts, 1830–1850, adding robustness to our reconstructions. Comparisons to additional documentary and proxy data sources are provided in a companion paper

Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care

ASD and schizophrenia show distinct developmental profiles in common genetic overlap with population-based social communication difficulties

Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and schizophrenia. Both conditions follow, however, distinct developmental patterns. Symptoms of ASD typically occur during early childhood, whereas most symptoms characteristic of schizophrenia do not appear before early adulthood. We investigated whether overlap in common genetic in fluences between these clinical conditions and impairments in social communication depends on the developmental stage of the assessed trait. Social communication difficulties were measured in typically-developing youth (Avon Longitudinal Study of Parents and Children,N⩽5553, longitudinal assessments at 8, 11, 14 and 17 years) using the Social Communication Disorder Checklist. Data on clinical ASD (PGC-ASD: 5305 cases, 5305 pseudo-controls; iPSYCH-ASD: 7783 cases, 11 359 controls) and schizophrenia (PGC-SCZ2: 34 241 cases, 45 604 controls, 1235 trios) were either obtained through the Psychiatric Genomics Consortium (PGC) or the Danish iPSYCH project. Overlap in genetic in fluences between ASD and social communication difficulties during development decreased with age, both in the PGC-ASD and the iPSYCH-ASD sample. Genetic overlap between schizophrenia and social communication difficulties, by contrast, persisted across age, as observed within two independent PGC-SCZ2 subsamples, and showed an increase in magnitude for traits assessed during later adolescence. ASD- and schizophrenia-related polygenic effects were unrelated to each other and changes in trait-disorder links reflect the heterogeneity of genetic factors in fluencing social communication difficulties during childhood versus later adolescence. Thus, both clinical ASD and schizophrenia share some genetic in fluences with impairments in social communication, but reveal distinct developmental profiles in their genetic links, consistent with the onset of clinical symptom