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Did the COVID-19 pandemic bring people together or push them apart? While infectious diseases tend to push people apart, crises can also bring people together through positive interdependence. We studied this question by asking an international sample (N = 1,006) about their inclinations to cooperate, perceptions of interdependence (i.e., shared fate), and perceived risk as well as local prevalence of COVID-19 infection across 14 time points from March to August, 2020. While perceived interdependence with others tended to increase during this time period, inclinations to cooperate decreased over time. At the within-person level, higher local prevalence of COVID-19 attenuated increases in perceived interdependence with others, and was associated with lower inclinations to cooperate. At the between-person level, people with high perceived interdependence with others reported more stable, or increasing, inclinations to cooperate over time than people with low perceived interdependence. Establishing a high sense of perceived interdependence with others may thus allow people to maintain cooperation during crises, even in the face of challenging circumstances such as those posed by a highly transmissible virus. [ABSTRACT FROM AUTHOR]

BackgroundMedulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines.MethodsIn this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma.FindingsWe included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes.InterpretationGenetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics.FundingGerman Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.

Background. Metabolic dysfunction‐associated steatohepatitis (MASH) has become the leading cause of chronic liver disease, but there has been no approved pharmacotherapy to date. Methods. We used a network analysis approach to delineate protein‐protein interactions that contribute to the transition from steatosis to MASH, in order to identify and target this transition as a potential pharmacotherapeutic strategy. Acyl‐CoA thioesterase 1 (ACOT1) was identified as a critical node in the protein‐protein interaction (PPI) network of the transition from steatosis to MASH in patient samples. ACOT1 overexpression and silencing effects were tested in vivo on C57BL/6 mice exposed to high‐fat diet (HFD) and inoculated with an adenoviral system to modulate ACOT1 expression. Transcriptomic and untargeted lipidomic profiles were performed on the mouse livers. Results. ACOT1 expression was 3‐fold higher in MASH as compared to steatosis. In patient samples, ACOT1 was significantly correlated with the severity of MASH as reflected by the nonalcoholic fatty liver disease score. Experimental validation showed that downregulation of ACOT1 resulted in decreased lipid accumulation and prevention of MASH in vivo. Conversely, upregulation of ACOT1 via an adenoviral vector resulted in development of MASH, whereas control mice only developed steatosis. Lipidomic analysis revealed glycerophospholipids to be especially abundant in MASH accelerated by ACOT1 upregulation. Conclusion. These results suggest that ACOT1 contributes to the transition from steatosis to MASH through modulation of glycerophospholipid accumulation and its potential as a novel therapeutic target in MASH. This trial is registered with NCT02148471. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic steatohepatitis (NASH) has become a leading indication for liver transplantation. However, it often recurs in the graft and can also arise de novo in individuals transplanted for other indications. Posttransplant NASH (PT-NASH) is more aggressive and leads to accelerated fibrosis. The mechanistic basis of PT-NASH has not yet been defined and no specific therapeutic strategies are currently available. Methods: Here, we profiled the transcriptomes of livers with PT-NASH from liver transplant recipients to identify dysregulated genes, pathways, and molecular interaction networks. Results: Transcriptomic changes in the PI3K-Akt pathway were observed in association with metabolic alterations in PT-NASH. Other significant changes in gene expression were associated with DNA replication, cell cycle, extracellular matrix organization, and wound healing. A systematic comparison with nontransplant NASH (NT-NASH) liver transcriptomes indicated an increased activation of wound healing and angiogenesis pathways in the post-transplant condition. Conclusion: Beyond altered lipid metabolism, dysregulation of wound healing and tissue repair mechanisms may contribute to the accelerated development of fibrosis associated with PT-NASH. This presents an attractive therapeutic avenue to explore for PT-NASH to optimize the benefit and survival of the graft. [ABSTRACT FROM AUTHOR]

Defining the ontogeny of tumor-associated macrophages (TAM) is important to develop therapeutic targets for mesothelioma. We identified two distinct macrophage populations in mouse peritoneal and pleural cavities, the monocyte-derived, small peritoneal/pleural macrophages (SPM), and the tissue-resident large peritoneal/pleural macrophages (LPM). SPM rapidly increased in tumor microenvironment after tumor challenge and contributed to the vast majority of M2-like TAM. The selective depletion of M2-like TAM by conditional deletion of the Dicer1 gene in myeloid cells (D−/−) promoted tumor rejection. Sorted SPM M2-like TAM initiated tumorigenesis in vivo and in vitro, confirming their capacity to support tumor development. The transcriptomic and single-cell RNA sequencing analysis demonstrated that both SPM and LPM contributed to the tumor microenvironment by promoting the IL-2-STAT5 signaling pathway, inflammation, and epithelial–mesenchymal transition. However, while SPM preferentially activated the KRAS and TNF-α/NFkB signaling pathways, LPM activated the IFN-γ response. The importance of LPM in the immune response was confirmed by depleting LPM with intrapleural clodronate liposomes, which abrogated the antitumoral memory immunity. SPM gene signature could be identified in pleural effusion and tumor from patients with untreated mesothelioma. Five genes, TREM2, STAB1, LAIR1, GPNMB, and MARCO, could potentially be specific therapeutic targets. Accordingly, Trem2 gene deletion led to reduced SPM M2-like TAM with compensatory increase in LPM and slower tumor growth. Overall, these experiments demonstrate that SPM M2-like TAM play a key role in mesothelioma development, while LPM more specifically contribute to the immune response. Therefore, selective targeting of monocyte-derived TAM may enhance antitumor immunity through compensatory expansion of tissue-resident TAM. [ABSTRACT FROM AUTHOR]

Long‐term survival of transplant recipients is significantly impacted by malignancy. We aimed to determine whether calcineurin inhibitor (CNI)‐treated recipients converted to and weaned off molecular target of rapamycin inhibitor (mTOR‐I) therapy have favorable changes in their molecular profiles in regard to malignancy risk. We performed gene expression profiling from liver biopsy and blood (PBMC) specimens followed by network analysis of key dysregulated genes, associated diseases and disorders, molecular and cellular functions using IPA software. Twenty non‐immune, non‐viremic patients were included, and 8 of them achieved tolerance. Two comparisons were performed: (1) tolerance time point vs tacrolimus monotherapy and (2) tolerance time point vs sirolimus monotherapy. Upon achieving tolerance, IPA predicted significant activation of DNA damage response (p = 5.40e‐04) and inhibition of DNA replication (p = 7.56e‐03). Conversion from sirolimus to tolerance showed decrease in HCC (p = 1.30e‐02), hepatic steatosis (p = 5.60e‐02) and liver fibrosis (p = 2.91e‐02) associated genes. In conclusion, this longitudinal study of patients eventually achieving tolerance reveals an evolving molecular profile associated with decreased cancer risk and improved hepatic steatosis and liver fibrosis. This provides a biological rationale for attempting conversion to mTOR‐I therapy and tolerance following liver transplantation particularly in patients at higher risk of cancer incidence and progression post‐transplant. [ABSTRACT FROM AUTHOR]

Donations represent an important contribution to the development of cultural and scientific heritage, as well as to the preservation of local and national cultural memory. The local collection fund is unique, and original, characteristic of every county or municipal public library, the whole of the collections being built starting from this part of essential local memory. The patrimonial collections of the libraries include old funds (older than 100 years), rare or precious, but also local funds and collections established through Legal Deposit. A donation to the heritage fund of the County Library ‟Dinicu Golescu" Argeș is the donation of a remarkable historian of Pitești, prof. univ. dr. Petre Popa and his wife, prof. Livia Popa. The donation consists of volumes of literature and literary criticism, history, culture and civilization, author's works, but also works received from other writers, most of the books with autographs and dedications, all books containing ex-libris and the stamp specifying ‟Donation for the Library Argeș County, date and number". [ABSTRACT FROM AUTHOR]

Cultural and scientific heritage expresses a nation's identity and its contribution to the world's heritage. The library's mission has always been inextricably linked to the documentary heritage, to all the activities of building, processing, preserving and enhancing the heritage, and to ensuring its integrity and access for future generations. Donation is the oldest way of adding to a library's holdings, with most libraries being set up through a donation, either a monetary donation or the donation of an entire collection or library belonging to a personality. It is not known whether the way of donating documents worked in antiquity, but from the Middle Ages onwards, donation was often the main way of increasing the number of books in publicly accessible libraries. Such valuable donations from royal libraries, princely libraries, private collections, manorial and monastery libraries, inherited for centuries and built up from a heritage perspective, today represent the old, rare and precious holdings of our libraries. In Romania, two directions of development of the documentary heritage approach have emerged: on the one hand, an awareness of the invaluable and irreplaceable value of the documentary collections handed down from generation to generation for the history and culture of the Romanian people, and on the other hand, a concept and methodology of conservation and restoration. [ABSTRACT FROM AUTHOR]

Abstract Background Sporadic Amyotrophic Lateral Sclerosis (sALS) is a devastating, complex disease of unknown etiology. We studied this disease with microarray technology to capture as much biological complexity as possible. The Affymetrix-focused BaFL pipeline takes into account problems with probes that arise from physical and biological properties, so we adapted it to handle the long-oligonucleotide probes on our arrays (hence LO-BaFL). The revised method was tested against a validated array experiment and then used in a meta-analysis of peripheral white blood cells from healthy control samples in two experiments. We predicted differentially expressed (DE) genes in our sALS data, combining the results obtained using the TM4 suite of tools with those from the LO-BaFL method. Those predictions were tested using qRT-PCR assays. Results LO-BaFL filtering and DE testing accurately predicted previously validated DE genes in a published experiment on coronary artery disease (CAD). Filtering healthy control data from the sALS and CAD studies with LO-BaFL resulted in highly correlated expression levels across many genes. After bioinformatics analysis, twelve genes from the sALS DE gene list were selected for independent testing using qRT-PCR assays. High-quality RNA from six healthy Control and six sALS samples yielded the predicted differential expression for 7 genes: TARDBP, SKIV2L2, C12orf35, DYNLT1, ACTG1, B2M, and ILKAP. Four of the seven have been previously described in sALS studies, while ACTG1, B2M and ILKAP appear in the context of this disease for the first time. Supplementary material can be accessed at: http://webpages.uncc.edu/~cbaciu/LO-BaFL/supplementary_data.html. Conclusion LO-BaFL predicts DE results that are broadly similar to those of other methods. The small healthy control cohort in the sALS study is a reasonable foundation for predicting DE genes. Modifying the BaFL pipeline allowed us to remove noise and systematic errors, improving the power of this study, which had a small sample size. Each bioinformatics approach revealed DE genes not predicted by the other; subsequent PCR assays confirmed seven of twelve candidates, a relatively high success rate.

"Dinicu Golescu" County Library Argeș has enriched its collections over time, through acquisitions of Romanian and foreign documents, but also through donations, these having a significant share in supplementing the collections, many documents being of great value, with an importance special for our cultural and national identity. Among the valuable book donations that belonged to prestigious donors, important people of Romanian political, social and cultural life are that of Elena Perticari-Davila, great-granddaughter, through her mother, of the scholar Dinicu Golescu, daughter of the famous military doctor Carol Davila and of Anica Racoviță, author of memorial volumes and translator of literary works. The memorial work of the writer Elena Perticari-Davila is an admirable fresco of the Goleşti mansion, shrouded in the romantic aura of a past of legendary greatness. The Elena Perticari-Davila donation in the collections of the Argeș County Library includes 89 books, most written in French and a few in Romanian, of which 38 books are in the Special Collections section and 51 books in the General collections. It is a pride that a large part of the valuable library in Izvoru of Mrs. Elena Perticari-Davila is part of the collections of the County Library "Dinicu Golescu" Argeș. The patrimonial function, mainly reflected by the preoccupations for the preservation of rare, bibliophile documents, with historical, cultural, scientific value, remains a constant preoccupation of the Argeș County Library. [ABSTRACT FROM AUTHOR]