Redox Regulation, Rather than Stress-Induced Phosphorylation, of a Hog1 Mitogen-Activated Protein Kinase Modulates Its Nitrosative-Stress-Specific Outputs

Data availability. The RNA sequencing dataset is available at EBI (www.ebi.ac.uk/arrayexpress/) under accession number E-MTAB-5990. Other data that support the findings of this study are available from the corresponding author upon reasonable request. ACKNOWLEDGMENTS We thank Debbie Smith for constructing the strains JC41 and JC310, Arnab Pradhan for help with DHE control experiments, and our colleagues in the Aberdeen Fungal Group and Newcastle Yeast Group for insightful discussions. We are also grateful to Mike Gustin for his advice. We are grateful to the Centre for Genome Enabled Biology and Medicine, Aberdeen Proteomics, the Iain Fraser Cytometry Centre, the Microscopy and Histology Facility, and the qPCR facility at the University of Aberdeen for their help, advice, and support. This work was funded by the UK Biotechnology and Biological Research Council (http://www.bbsrc.ac.uk) (grants BB/K017365/1 and BB/F00513X/1 to A.J.P.B. and grant BB/K016393/1 to J.Q.). This work was also supported by the European Research Council (http://erc.europa.eu/) (STRIFE advanced grant C-2009-AdG-249793 to A.J.P.B.), the UK Medical Research Council (http://www.mrc.ac.uk) (grant MR/M026663/1 to A.J.P.B. and grant MR/M000923/1 to P.S.S.), the Wellcome Trust (https://wellcome.ac.uk) (grant 097377 to A.J.P.B. and J.Q.), the MRC Centre for Medical Mycology and the University of Aberdeen (grant MR/M026663/1 to A.J.P.B.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Integrative Model of Oxidative Stress Adaptation in the Fungal Pathogen Candida albicans

Acknowledgments We are grateful to the Ian Fraser Cytometry Centre and our Mass Spetrometry and qPCR Facilities for help with the flow cytometry, glutathione and qRT-PCR assays, respectively. We also thank our many colleagues in the CRISP Consortium and in the medical mycology and systems biology communities for insightful discussions. Funding: This work was supported by the CRISP project (Combinatorial Responses In Stress Pathways), which was funded by the UK Biotechnology and Biological Research Council (www.bbsrc.ac.uk): AJPB, KH, CG, ADM, NARG, MT, MCR. (Research Grants; BB/F00513X/1, BB/F005210/1-2). AJPB and JQ received additional support from the BBSRC (Research Grants; BB/K016393/1; BB/K017365/1). NARG and AJPB were also supported by the Wellcome Trust (www.wellcome.ac.uk), (Grants: 080088; 097377). AJPB was also supported by the European Research Council (http://erc.europa.eu/), (STRIFE Advanced Grant; ERC-2009-AdG-249793). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Optimization of a home hospitalization program for hematopoietic stem cell transplantation with ehealth integration and clinical pharmacist involvement

Home hospitalization represents an alternative to traditional hospitalization, providing comparable clinical safety for hematological patients. At-home therapies can range from the delivery of intravenous antibiotics to more complex scenarios, such as the care during the early period after hematopoietic stem cell transplantation and chimeric antigen receptor T-cell therapy. Early discharge from conventional hospitalization is feasible and helps reduce hospital resources and waiting lists. The coordinated efforts of multidisciplinary teams, including hematologists, nurses, and pharmacists, ensure patient safety and continuity of care. The traditional model of home hospitalization relies on home visits and telephone consultations with physicians and nurses. However, the use of eHealth technologies, such as MY-Medula, can enhance communication and monitoring, and thereby improve patient outcomes with no additional costs. The active involvement of a clinical pharmacist in home hospitalization programs is essential, not only for the proper logistical management of the medication but also to ensure its appropriateness, optimize treatment, address queries from the team and patients, and promote adherence. In conclusion, the implementation of hematopoietic stem cell transplantation and chimeric antigen receptor T-cell therapy home hospitalization programs that use both an eHealth tool and a multidisciplinary care model can optimize patient care and improve quality of life without increasing healthcare costs

Comparison of First-Pass Effect in Aspiration vs. Stent-Retriever for Acute Intracranial ICA Occlusion

The purpose of this study is to evaluate the best endovascular approach (aspiration or stent-retriever) and the impact of stent retriever size and length on clinical and angiographic outcomes in patients with acute intracranial ICA occlusion. We conducted a retrospective analysis of a prospective database of consecutive patients with acute intracranial ICA occlusion undergoing endovascular treatment in four Comprehensive Stroke Center between June-2019 and December-2020. We include 121 patients; Stent-retriever (SR) was used as first technical approach in 107 patients (88.4%) and aspiration was used in 14 patients (11.6%). SR group had higher rate of FPE compared to aspiration group (29 vs. 0%, p = 0.02). In SR subgroup, treatment highlighted higher FPE in the 6 x 50 SR (37.7%), than in the rest of the SR which are 21.2% (4-5 mm size and 20-50 mm length SR) and 19% (6 mm size and 25-40 mm length SR), but it was not found to be statistically significant. There were no other significant differences across the groups regarding primary angiographic or clinical outcomes. In our intracranial ICA occlusion series, stent retrievers were superior to direct aspiration in obtaining FPEs and mFPEs, and longer devices achieved better results with no statistically significant difference. Further studies evaluating the effects of different ICA clot removal approaches are warranted to confirm these results

Tratamientos habituales utilizados en cefaleas, neuralgias y SARS-CoV-2. Posicionamiento del grupo de estudio de cefaleas de la Sociedad Española de Neurología

Introducción: En los últimos meses han surgido dudas por parte de pacientes, médicos de familia y neurólogos sobre la posibilidad de que algunos de los fármacos que habitualmente se utilizan en cefaleas y neuralgias puedan facilitar o complicar la infección por el SARS-CoV-2. Material y métodos: Hemos recabado información sobre el posicionamiento de sociedades científicas, así como de las distintas Agencias de Medicamentos (americana, europea y española) para poder esclarecer dudas respecto al uso de fármacos como lisinopril, candesartán, ibuprofeno, corticoides, carbamazepina, anticuerpos monoclonales contra el péptido relacionado con el gen de la calcitonina (CGRP) durante la pandemia por COVID-19. Resultados: Planteamos recomendaciones acerca del uso de fármacos habituales en el tratamiento de las cefaleas en el contexto de la pandemia por COVID-19, basándonos en las evidencias de las que disponemos en el momento actual. Conclusiones: Actualmente no existe ningún argumento científico robusto para contraindicar formalmente ninguno de los tratamientos que se emplean en cefaleas y neuralgias

Genomic analysis of 18th-century kazakh individuals and their oral microbiome

The Asian Central Steppe, consisting of current-day Kazakhstan and Russia, has acted as a highway for major migrations throughout history. Therefore, describing the genetic composition of past populations in Central Asia holds value to understanding human mobility in this pivotal region. In this study, we analyse paleogenomic data generated from five humans from Kuygenzhar, Kazakhstan. These individuals date to the early to mid-18th century, shortly after the Kazakh Khanate was founded, a union of nomadic tribes of Mongol Golden Horde and Turkic origins. Genomic analysis identifies that these individuals are admixed with varying proportions of East Asian ancestry, indicating a recent admixture event from East Asia. The high amounts of DNA from the anaerobic Gram-negative bacteria Tannerella forsythia, a periodontal pathogen, recovered from their teeth suggest they may have suffered from periodontitis disease. Genomic analysis of this bacterium identified recently evolved virulence and glycosylation genes including the presence of antibiotic resistance genes predating the antibiotic era. This study provides an integrated analysis of individuals with a diet mostly based on meat (mainly horse and lamb), milk, and dairy products and their oral microbiome.C.L.-F. is supported by a PGC2018-0955931-B-100 grant (MCIU/AEI/FEDER, UE) of Spain; T.M.-B. is supported by funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 864203), BFU2017-86471-P (MINECO/FEDER, UE), “Unidad de Excelencia María de Maeztu”, funded by the AEI (CEX2018-000792-M), Howard Hughes International Early Career, Secretaria d’Universitats i Recerca and CERCA Programme del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 880). L.v.D. is supportd by a UCL Excellence Fellowship. The Ministry of the Education and Science of the Republic of Kazakhstan permitted and granted the research and the study (Grant number AP09261134). Additional financial contribution was provided by the ISMEO of Rome

Primary constitutional MLH1 epimutations: a focal epigenetic event

BACKGROUND: Constitutional MLH1 epimutations are characterised by monoallelic methylation of the MLH1 promoter throughout normal tissues, accompanied by allele-specific silencing. The mechanism underlying primary MLH1 epimutations is currently unknown. The aim of this study was to perform an in-depth characterisation of constitutional MLH1 epimutations targeting the aberrantly methylated region around MLH1 and other genomic loci. METHODS: Twelve MLH1 epimutation carriers, 61 Lynch syndrome patients, and 41 healthy controls, were analysed by Infinium 450 K array. Targeted molecular techniques were used to characterise the MLH1 epimutation carriers and their inheritance pattern. RESULTS: No nucleotide or structural variants were identified in-cis on the epimutated allele in 10 carriers, in which inter- generational methylation erasure was demonstrated in two, suggesting primary type of epimutation. CNVs outside the MLH1 locus were found in two cases. EPM2AIP1-MLH1 CpG island was identified as the sole differentially methylated region in MLH1 epimutation carriers compared to controls. CONCLUSION: Primary constitutional MLH1 epimutations arise as a focal epigenetic event at the EPM2AIP1-MLH1 CpG island in the absence of cis-acting genetic variants. Further molecular characterisation is needed to elucidate the mechanistic basis of MLH1 epimutations and their heritability/reversibility

Antimalarial Activity and Mechanisms of Action of Two Novel 4-Aminoquinolines against Chloroquine-Resistant Parasites

Chloroquine (CQ) is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index). However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax. Despite CQ resistance, novel drug candidates based on the structure of CQ continue to be considered, as in the present work. One CQ analog was synthesized as monoquinoline (MAQ) and compared with a previously synthesized bisquinoline (BAQ), both tested against P. falciparum in vitro and against P. berghei in mice, then evaluated in vitro for their cytotoxicity and ability to inhibit hemozoin formation. Their interactions with residues present in the NADH binding site of P falciparum lactate dehydrogenase were evaluated using docking analysis software. Both compounds were active in the nanomolar range evaluated through the HRPII and hypoxanthine tests. MAQ and BAQ derivatives were not toxic, and both compounds significantly inhibited hemozoin formation, in a dose-dependent manner. MAQ had a higher selectivity index than BAQ and both compounds were weak PfLDH inhibitors, a result previously reported also for CQ. Taken together, the two CQ analogues represent promising molecules which seem to act in a crucial point for the parasite, inhibiting hemozoin formation

The population genomic legacy of the second plague pandemic

Human populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1,347 CE and repeatedly returned for over 300 years, with typical village and town mortality estimated at 10%–40%.1 It is assumed that this high mortality affected the gene pools of these populations. First, local population crashes reduced genetic diversity. Second, a change in frequency is expected for sequence variants that may have affected survival or susceptibility to the etiologic agent (Yersinia pestis).2 Third, mass mortality might alter the local gene pools through its impact on subsequent migration patterns. We explored these factors using the Norwegian city of Trondheim as a model, by sequencing 54 genomes spanning three time periods: (1) prior to the plague striking Trondheim in 1,349 CE, (2) the 17th–19th century, and (3) the present. We find that the pandemic period shaped the gene pool by reducing long distance immigration, in particular from the British Isles, and inducing a bottleneck that reduced genetic diversity. Although we also observe an excess of large FST values at multiple loci in the genome, these are shaped by reference biases introduced by mapping our relatively low genome coverage degraded DNA to the reference genome. This implies that attempts to detect selection using ancient DNA (aDNA) datasets that vary by read length and depth of sequencing coverage may be particularly challenging until methods have been developed to account for the impact of differential reference bias on test statistics.publishedVersio

The population genomic legacy of the second plague pandemic

Human populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1,347 CE and repeatedly returned for over 300 years, with typical village and town mortality estimated at 10%-40%.1 It is assumed that this high mortality affected the gene pools of these populations. First, local population crashes reduced genetic diversity. Second, a change in frequency is expected for sequence variants that may have affected survival or susceptibility to the etiologic agent (Yersinia pestis).2 Third, mass mortality might alter the local gene pools through its impact on subsequent migration patterns. We explored these factors using the Norwegian city of Trondheim as a model, by sequencing 54 genomes spanning three time periods: (1) prior to the plague striking Trondheim in 1,349 CE, (2) the 17th-19th century, and (3) the present. We find that the pandemic period shaped the gene pool by reducing long distance immigration, in particular from the British Isles, and inducing a bottleneck that reduced genetic diversity. Although we also observe an excess of large FST values at multiple loci in the genome, these are shaped by reference biases introduced by mapping our relatively low genome coverage degraded DNA to the reference genome. This implies that attempts to detect selection using ancient DNA (aDNA) datasets that vary by read length and depth of sequencing coverage may be particularly challenging until methods have been developed to account for the impact of differential reference bias on test statistics