Comprehensive genomic profiles of small cell lung cancer

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Dex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer

Geosciences Roadmap for Research Infrastructures 2025 - 2028 by the Swiss Geosciences Community

This roadmap is the product of a grassroots effort by the Swiss Geosciences community. It is the first of its kind, outlining an integrated approach to research facilities for the Swiss Geosciences. It spans the planning period 2025-2028. Swiss Geoscience is by its nature leading or highly in-volved in research on many of the major national and global challenges facing society such as climate change and meteorological extreme events, environmental pol-lution, mass movements (land- and rock-slides), earth-quakes and seismic hazards, global volcanic hazards, and energy and other natural resources. It is essential to under- stand the fundamentals of the whole Earth system to pro-vide scientific guidelines to politicians, stakeholders and society for these pressing issues. Here, we strive to gain efficiency and synergies through an integrative approach to the Earth sciences. The research activities of indivi- dual branches in geosciences were merged under the roof of the 'Integrated Swiss Geosciences'. The goal is to facilitate multidisciplinary synergies and to bundle efforts for large research infrastructural (RI) requirements, which will re-sult in better use of resources by merging sectorial acti- vities under four pillars. These pillars represent the four key RIs to be developed in a synergistic way to improve our understanding of whole-system processes and me- chanisms governing the geospheres and the interactions among their components. At the same time, the roadmap provides for the required transition to an infrastructure adhering to FAIR (findable, accessible, interoperable, and reusable) data principles by 2028.The geosciences as a whole do not primarily profit from a single large-scale research infrastructure investment, but they see their highest scientific potential for ground-break-ing new findings in joining forces in establishing state-of-the-art RI by bringing together diverse expertise for the benefit of the entire geosciences community. Hence, the recommendation of the geoscientific community to policy makers is to establish an integrative RI to support the ne- cessary breadth of geosciences in their endeavor to ad-dress the Earth system across the breadth of both temporal and spatial scales. It is also imperative to include suffi-cient and adequately qualified personnel in all large RIs. This is best achieved by fostering centers of excellence in atmospheric, environmental, surface processes, and deep Earth projects, under the roof of the 'Integrated Swiss Geosciences'. This will provide support to Swiss geo-sciences to maintain their long standing and internatio- nally well-recognized tradition of observation, monitor-ing, modelling and understanding of geosciences process-es in mountainous environments such as the Alps and beyond

Examining immune-inflammatory mechanisms of probiotic supplementation in depression: secondary findings from a randomized clinical trial

Abstract We recently indicated that four-week probiotic supplementation significantly reduced depression along with microbial and neural changes in people with depression. Here we further elucidated the biological modes of action underlying the beneficial clinical effects of probiotics by focusing on immune-inflammatory processes. The analysis included a total of N = 43 participants with depression, from which N = 19 received the probiotic supplement and N = 24 received a placebo over four weeks, in addition to treatment as usual. Blood and saliva were collected at baseline, at post-intervention (week 4) and follow-up (week 8) to assess immune-inflammatory markers (IL-1β, IL-6, CRP, MIF), gut-related hormones (ghrelin, leptin), and a stress marker (cortisol). Furthermore, transcriptomic analyses were conducted to identify differentially expressed genes. Finally, we analyzed the associations between probiotic-induced clinical and immune-inflammatory changes. We observed a significant group x time interaction for the gut hormone ghrelin, indicative of an increase in the probiotics group. Additionally, the increase in ghrelin was correlated with the decrease in depressive symptoms in the probiotics group. Transcriptomic analyses identified 51 up- and 57 down-regulated genes, which were involved in functional pathways related to enhanced immune activity. We identified a probiotic-dependent upregulation of the genes ELANE, DEFA4 and OLFM4 associated to immune activation and ghrelin concentration. These results underscore the potential of probiotic supplementation to produce biological meaningful changes in immune activation in patients with depression. Further large-scale mechanistic trials are warranted to validate and extend our understanding of immune-inflammatory measures as potential biomarkers for stratification and treatment response in depression. Trial Registration: www.clinicaltrials.gov , identifier: NCT02957591

Inbreeding in reintroduced populations: the effects of early reintroduction history and contemporary processes

Maintaining genetic variation and minimizing inbreeding are central goals of conservation genetics. It is therefore crucial to understand the important population parameters that affect inbreeding, particularly in reintroduction programs. Using data from 41 reintroduced Alpine ibex (Capra ibex ibex) populations we estimated inbreeding since the beginning of reintroductions using population-specific Fst, and inbreeding over the last few generations with contemporary effective population sizes. Total levels of inbreeding since reintroduction of ibex were, on average, close to that from one generation of half-sib mating. Contemporary effective population sizes did not reflect total inbreeding since reintroduction, but 16% of variation in contemporary effective population sizes among populations was due to variation in current population sizes. Substantial variation in inbreeding levels among populations was explained by founder group sizes and the harmonic mean population sizes since founding. This study emphasizes that, in addition to founder group sizes, early population growth rates are important parameters determining inbreeding levels in reintroduced populations

Zootermopsis nevadensis manual gene annotations

Manual gene annotation in gff3 format for the termite Zootermopsis nevadensis. Part of the manuscript "Hemimetabolous genomes reveal molecular basis of termite eusociality.

Macrotermes natalensis manual gene annotations

Manual gene annotation in gff3 format for the termite Macrotermes natalensis. Part of the manuscript "Hemimetabolous genomes reveal molecular basis of termite eusociality.

Comprehensive genomic profiles of small cell lung cancer

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Dex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer