8 research outputs found
Increased susceptibility to cardiovascular effects of dihydrocapcaicin in resuscitated rats. Cardiovascular effects of dihydrocapsaicin
No full textAbstract Background Survivors of a cardiac arrest often have persistent cardiovascular derangements following cardiopulmonary resuscitation including decreased cardiac output, arrhythmias and morphological myocardial damage. These cardiovascular derangements may lead to an increased susceptibility towards the external and internal environment of the cardiovascular system as compared to the healthy situation. Methods Here we tested the hypothesis that the cardiovascular system in healthy rats and rats resuscitated from a cardiac arrest may be differentially affected by a transient receptor potential vanilloid type 1 agonist, by continuous intravenous infusion of dihydrocapsaicin (DHC). Results Compared to baseline, infusion of DHC caused an initial increase in mean arterial blood pressure in both healthy and resuscitated rats of 25% and 10%, respectively. Also, we observed an initial response of tachycardia in both healthy and resuscitated rats of 30% and 20%, respectively. Then, at high levels of DHC infusion (> 2.0 mg/kg/hr) we observed two single episodes of transient bradycardia and hypotension in 33% of the healthy rats, which was consistent with a TRPV1 agonist induced Bezold-Jarisch reflex. In contrast, in resuscitated rats we observed multiple episodes of bradycardia/hypotension in 100% of the rats and at a dose of DHC of 0.65 mg/kg/hr. Notably, this DHC effect could be completely blocked in the resuscitated rats by pre-treatment with atropine, a muscarinic acetylcholine antagonist. Conclusions Our results indicate that the susceptibility of the rats towards TRPV1 agonist induced Bezold-Jarisch reflex is increased in those resuscitated from cardiac arrest compared to the healthy situation.</p
Phase Behaviour Of Oat β-Glucan/Sodium Caseinate Mixtures
No full textOat β-glucan is a water soluble polysaccharide which has been approved as a functional bioactive ingredient. In this thesis, β-glucan was successfully isolated from oat flour and samples of different molecular weights were produced. The structural features and molecular weights(Mw) were characterized by 13C–NMR spectroscopy and high performance size-exclusion chromatography, respectively. The rheological properties and microstructure of aqueous oat β-glucan solutions were investigated by rheometry and atomic force microscopy (AFM),respectively. The samples with β-glucan content between 78-86 % on a dry weight basis had Mw, intrinsic viscosity ([η]) and critical coil overlap concentration (c*) in the range of 142 - 2800 x 103 g/mol, 1.7 - 7.2 dL/g and 0.25 - 1.10 g/dL, respectively. The flow and viscoelasticvbehaviour was highly dependent on Mw and on the concentration of the β-glucan solutions. AFM images revealed the formation of cluster or aggregates linked via individual polymer chains scattered heterogeneously throughout the system. The aggregate size was also dependent on molecular weight of the samples and influences the rheological behaviour of β-glucan solutions. The isothermal phase behaviour at 5 oC of β-glucan/sodium caseinate mixtures were
investigated by means of phase diagram construction, rheometry, electrophoresis and fluorescence microscopy. Phase diagrams indicated that the compatibility of the β-glucan/sodium caseinate system increases as β-glucan Mw decreases. Images of the mixtures taken at various
biopolymer concentrations revealed phase separation with the presence of β-glucan aggregates,whose size depends on Mw and concentration. At the same protein concentration in the mixtures, the viscosity increases with increasing Mw and concentration of β-glucan. However, the results also revealed that in the state of thermodynamic equilibrium with comparable polymer concentrations in mixture, the lower Mw samples yielded similar or higher viscosity. At equivalent hydrodynamic volume of β-glucan component in the mixture, all the samples
exhibited similar viscosity/flow behaviour. A deviation dependent on the protein concentration
was observed for the high Mw sample in the concentrated regime due to the size of the β-glucan aggregates formed. Results demonstrate that by controlling the structural features of β-glucan in mixture with sodium caseinate, informed manipulation of rheological properties in these systems can be achieved
Drug-induced mild therapeutic hypothermia obtained by administration of a transient receptor potential vanilloid type 1 agonist
No full textAbstract Background The use of mechanical/physical devices for applying mild therapeutic hypothermia is the only proven neuroprotective treatment for survivors of out of hospital cardiac arrest. However, this type of therapy is cumbersome and associated with several side-effects. We investigated the feasibility of using a transient receptor potential vanilloid type 1 (TRPV1) agonist for obtaining drug-induced sustainable mild hypothermia. Methods First, we screened a heterogeneous group of TRPV1 agonists and secondly we tested the hypothermic properties of a selected candidate by dose-response studies. Finally we tested the hypothermic properties in a large animal. The screening was in conscious rats, the dose-response experiments in conscious rats and in cynomologus monkeys, and the finally we tested the hypothermic properties in conscious young cattle (calves with a body weight as an adult human). The investigated TRPV1 agonists were administered by continuous intravenous infusion. Results Screening: Dihydrocapsaicin (DHC), a component of chili pepper, displayed a desirable hypothermic profile with regards to the duration, depth and control in conscious rats. Dose-response experiments: In both rats and cynomologus monkeys DHC caused a dose-dependent and immediate decrease in body temperature. Thus in rats, infusion of DHC at doses of 0.125, 0.25, 0.50, and 0.75 mg/kg/h caused a maximal ΔT (°C) as compared to vehicle control of -0.9, -1.5, -2.0, and -4.2 within approximately 1 hour until the 6 hour infusion was stopped. Finally, in calves the intravenous infusion of DHC was able to maintain mild hypothermia with ΔT > -3°C for more than 12 hours. Conclusions Our data support the hypothesis that infusion of dihydrocapsaicin is a candidate for testing as a primary or adjunct method of inducing and maintaining therapeutic hypothermia.</p
Avaliação dos efeitos citotóxicos de cardenolídeos em células tumorais
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde. Programa de Pós-Graduação em FarmáciaOs cardenolídeos são metabólitos secundários encontrados na natureza e assim denominados em razão de sua ação inibitória na bomba de Na+/K+ (Na+/K+ATPase) e decorrentes efeitos sobre o músculo cardíaco. Por esta razão, cardenolídeos, tais como digoxina, digitoxina e ouabaína, são clinicamente utilizados para o tratamento da insuficiência cardíaca congestiva e algumas arritmias atriais. Nos últimos anos, vários estudos relataram a potencial atividade citotóxica, antitumoral e anticâncer de alguns cardenolídeos. Mundialmente, o câncer de pulmão é um dos principais responsáveis pela alta taxa de mortalidade atribuída ao câncer. O tratamento atual deste câncer depende do estágio do paciente e são utilizadas abordagens combinadas ou individuais, tais como excisão cirúrgica, radioterapia e quimioterapia. A taxa de sobrevivência dos pacientes, no entanto, não é elevada, tornando a busca por novos agentes no combate a este câncer uma necessidade. Neste trabalho, foi realizada uma triagem citotóxica, em células tumorais humanas A549, com 64 cardenolídeos e um dos compostos mais citotóxicos (CI50<100 nM) foi selecionado para investigação do seu mecanismo de ação, através de vários ensaios. Este composto, que se apresentou mais tóxico e mais seletivo para células tumorais foi o glucoevatromonosídeo e para a avaliação de seu mecanismo de ação uma série de ensaios foi realizada. Inicialmente, ele provocou o bloqueio do ciclo celular na fase G2/M, o que foi atribuído à diminuição da expressão da proteína ciclina B1, necessária para a progressão do ciclo celular. A indução de morte celular, por ele causada, não ocorreu por apoptose ou necrose, sendo provavelmente por autofagia, processo observado com a marcação de partículas acídicas, características deste tipo de morte celular. O envolvimento deste composto em vias de sinalização de morte celular foi constatado por alterações na expressão de proteínas das vias AKT, MAPK e NF-?B. Por fim, a atividade anti-ATPásica detectada não mostrou correlação da inibição desta enzima com a atividade citotóxica apresentada pelos compostos selecionados na triagem. A citotoxicidade promissora do glucoevatromonosídeo foi investigada e confirmada sua indução de morte celular independente de apoptose em células A549.Cardenolides are secondary metabolites found in nature and named after their known inhibitory action on the sodium pump (Na+/K+ATPase), and effect on the heart muscle. For this reason cardenolides as digoxin, digitoxin and ouabain are used in the treatment of congestive heart failure and atrial arrhythmias. In the past years, many were the reports on the citotoxic, antitumoral and anticancer activities of cardenolides. Lung cancer is one of the leading causes of death by cancer worldwide. Current treatment of lung cancer depends on the stage of the patient and both combined and individual approaches are used, such as surgery, radiotherapy and chemotherapy. However, the observed survival rate is not high, which stimulates the search for new agents for the treatment of this cancer. In the present work a cytotoxic screening with 64 cardenolides was performed and the most cytotoxic compound selected (CI50<100 nM) to further investigate its mechanism of action. The most cytotoxic and selective compound for cancer cell lines was glucoevatromonoside and to evaluate its mechanism of action a series of assays was carried out. Initially, this compound was able to block phase G2/M of cell cycle, which was attributed to the decrease in the expression of cyclin B1 protein, essential to the cell cycle progression. The investigation of the cytotoxic effect of this compound showed that the induced cell death was not apoptosis or necrosis mediated, and so might be through autophagy, as observed with the acridine orange marked acidic particles, a characteristic event of this type of cell death. Involvement of this compound in signaling pathways was verified through its ability to trigger alterations in the expression of AKT, MAPK and NF-?B proteins. The detected anti ATPase activity did not show correlation of the enzyme inhibition with the cytotoxic activity presented by the compounds selected in the screening. Hereby, the promising cytotoxic activity of glucoevatromonoside was investigated and confirmed its apoptosis-independent cell death induction in A549 cells. It was suggested that cell death was caused by cell cycle arrest and autophagy induction with signaling pathways involved
Publisher Correction: Populatiosn genomics of post-glacial western Eurasia (Nature, (2024), 625, 7994, (301-311), 10.1038/s41586-023-06865-0)
No full textCorrection to: Nature Published online 10 January 2024 In the version of this article initially published, there were errors in the second affiliations for Levon Yepiskoposyan (Russian-Armenian University, Yerevan, Armenia) and Sergey Vasilyev (Center for Egyptological Studies, Russian Academy of Sciences, Moscow, Russian Federation), and in the first affiliation for Ruben Badalyan (Institute of Archaeology and Ethnography, National Academy of Sciences, Yerevan, Armenia); the affiliations are amended in the HTML and PDF versions of the article. © 2024, The Author(s)
Effect of anastrozole on bone mineral density and lipid profiles when used to prevent breast cancer in high risk postmenopausal women
No full textPhDThe role of aromatase inhibitors (AIs) in breast cancer has expanded since their introduction in
the mid-1990s. They are superior to tamoxifen in the treatment of postmenopausal women with
oestrogen dependant tumours in the metastatic, neoadjuvant, and adjuvant settings and are
currently been explored as chemopreventive agents. When compared to tamoxifen they are
known to reduce bone mineral density (BMD), increase fracture rate, increase joint symptoms,
and may also increase the risk of cardiovascular disease. The International Breast Cancer
Intervention Study-II (IBIS-II) is the only breast cancer prevention randomised trial studying
the role of anastrozole versus placebo in preventing breast cancer in postmenopausal women
with a high risk of breast cancer.
Methods
This thesis focus on four main areas: (a) Analysis of data from the bone sub-study of the IBISII
study, exploring the effects of anastrozole on bone mineral density at 12 and 36-months, and
the ability of bisphosphonates treatment to reduce bone loss in women with low mineral density
(BMD) at baseline. (b) Analysis of data from the prevention stratum of the IBIS-II study,
exploring the effect of anastrozole on cholesterol fractions. (c) Analysis of the data from the
Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, exploring different risk factors
for fractures in women with breast cancer who received either anastrozole or tamoxifen for five
years (d) Analysis of data from the prevention stratum of the IBIS-II study, exploring if baseline
25(OH) vitamin D levels predicted arthralgia within one year of study.
Results
Women with normal BMD at baseline had a significant BMD loss at lumbar spine and total hip
for both anastrozole and placebo. However, the BMD loss at lumbar spine was significantly
11
greater with anastrozole. Osteopenic women, who received anastrozole plus risedronate, after
12-months of treatment gained significant bone density at lumbar spine compared to women
receiving anastrozole without risedronate, but not at total hip. At 36 months, there was no
significant gain in bone density either at lumbar spine or total hip. In osteoporotic women,
risedronate abrogated the detrimental effect of anastrozole, after 12 months of treatment,
significantly at lumbar spine, but not at total hip. After 36 months of treatment, risedronate still
abrogated the effect of anastrozole at lumbar spine, but not significantly. These 12 and 36-
months data suggest that bone loss associated with anastrozole may be manageable with DXA
monitoring and bisphosphonate use.
Use of anastrozole did not lead to any significant changes in total cholesterol and high-density
lipoprotein cholesterol levels when compared with placebo, except that anastrozole marginally
decreased TC levels. These data support the lack of cardiovascular toxicity with anastrozole
seen in the adjuvant trials.
Using a model containing the following risk factors; age, weight/height/BMI, geographical
regions, smoking, use of statins and other medication at baseline, previous chemotherapy,
previous radiotherapy and trial therapy, only treatment, age and geographical regions were
found to be significantly associated with fracture risk.
No significant effect of baseline vitamin D levels were seen on the risk of musculoskeletal
symptoms in healthy postmenopausal women at a high risk of breast cancer. The serum 25 (OH)
vitamin D levels significantly increased in the anastrozole group from baseline to 12 months,
when compared with placebo
Adipose tissue derived factors in obesity, inflammation & energy homeostasis
No full textObesity is the foremost contributory factor in the progression to type 2 diabetes
mellitus (T2DM). Moreover, chronic inflammation, through activation of innate
immunity is proposed to link obesity, insulin resistance and T2DM. Adipose tissue,
traditionally considered a storage compartment for triglycerides, also functions as an
active endocrine organ. Adipocyte-secreted products, termed adipokines, may link
obesity-associated inflammation and insulin resistance. Adipokines exert multiple
effects on insulin sensitisation, glucose homeostasis, inflammatory processes or
central systems mediating energy expenditure. This thesis principally examined two
adipokines; resistin and adiponectin. Resistin and components of innate immunity
were assessed in human obesity. In-vitro analysis established that resistin was
expressed and secreted by human adipocytes. Furthermore, key factors in the innate
immune pathway were highly expressed in obese and T2DM adipose tissue. This
thesis further explored the pro-inflammatory actions of resistin in adipocytes. Resistin
stimulated the secretion of inflammatory cytokines from adipocytes and, the
expression of key intermediates of the innate immune and insulin signalling pathways.
Clinical studies entailed examination of resistin as a marker of inflammation in
childhood obesity. Serum analysis revealed gender-differences in resistin levels in
obese children. Furthermore, bacterial endotoxin correlated with several markers of
inflammation and cardiovascular disease; suggesting endotoxin as a contributor to
inflammation in childhood obesity. This thesis subsequently examined another
adipokine, adiponectin; considered to have a `ying-and-yang' relationship with
resistin. Studies explored a central role for adiponectin in energy homeostasis. Gelfiltration
liquid chromatography established that the adiponectin trimer was
predominant in human cerebrospinal fluid. Such identification of trimeric adiponectin
in vivo implicates the pharmacologically generated globular adiponectin in central
regulation of energy expenditure. In conclusion, resistin may serve as a pathogenic
pro-inflammatory factor, exacerbating inflammation within adipose tissue; potentially
contributing to the progression of obesity-driven T2DM. Alternatively, adiponectin
may have favourable central actions, influencing energy expenditure through its basic
trimeric form. Collectively, this thesis suggests that resistin and adiponectin, with a
range of opposing properties, may substantially affect whole-body metabolism
Population genomics of post-glacial western Eurasia
No full textWestern Eurasia witnessed several large-scale human migrations during the Holocene1–5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 bp, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 bp, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a ‘Neolithic steppe’ cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations. © 2024, The Author(s).Marie Skłodowska-Curie Actions of the EU; Swedish Foundation for Humanities and Social Sciences; Kazakhstan–Central Asia; Ural Federal University Program of Development; Lundbeck Foundation GeoGenetics Centre; Aarhus Universitets Forskningsfond; European Research Council, ERC; Ministry of Science and Higher Education of the Russian Federation; National Institute on Aging, NIA; St John’s College, Cambridge; Danmarks Grundforskningsfond, DNRF, (DNRF94, DNRF174); Generalitat Valenciana, GVA, (CIDEGENT/2019/061); H2020 Marie Skłodowska-Curie Actions, MSCA, (751349, R335-2019-2318); Wellcome Trust, WT, (214300, 214300); , (949424, 846856, 681605, 679330, 300554); Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, SNF, (SFNS PP00P3_176977); European Union’s Horizon Europe programme, (R248-2017-2003, 101077592); Riksbankens Jubileumsfond, RJ, (M16-0455:1); NOMIS Stiftung, (АР09261083); Ministerio de Ciencia e Innovación, MICINN, (HAR2017-86262-P, HAR2016-75605-R); Ferring Pharmaceuticals, (R102-A9118, R155-2014-1724); Àrainneachd Eachdraidheil Alba, AEA, (075-15-2022-328, AR08856925); Social Sciences and Humanities Research Council of Canada, SSHRC, (G101449); Spanish Government, (EUR2020-112213); Carlsbergfondet, (CF18-0024); Villum Fonden, (17649, 10120); National Institute of General Medical Sciences, NIGMS, (CF19-0712, R35GM142916, NNF14CC0001, R01GM138634, 00025300); Ministry of Education and Science of the Republic of Kazakhstan, (AP08856317); Danmarks Frie Forskningsfond, DFF, (7027-00147B); Lundbeck Foundation, (R302-2018-2155, R155-2013-16338); Novo Nordisk Fonden Data Science Ascending, (NNF22OC0076816); National Institutes of Health, NIH, (U24AG051129, U19AG023122, UH2AG064706); Novo Nordisk Fonden, NNF, (NNF18SA0035006); ERC-Starter, (CF19-0601); Ministry of Education and Science, (21AG-1F025, 075-15-2021-1069); Københavns Universitet, KU, (KU2016); Ministerio de Economía y Competitividad, MINECO, (Aico 2020/97, HAR2013‐46861‐R, Aico/ 2018/125)Funding text 1: We acknowledge P. Bennike, who was involved in initiating this project, for her substantial contributions to its conception and to prehistoric research more broadly; she passed away in 2017. We thank L. Olsen and P. Selmer Olsen for administrative and technical assistance, respectively; the UK Biobank for access to the UK Biobank genomic resource; Illumina for collaboration; and S. Ellingv\u00E5g for assistance with sample access. E.W. thanks St John\u2019s College, Cambridge, for providing a stimulating environment of discussion and learning. The Lundbeck Foundation GeoGenetics Centre is supported by grants from the Lundbeck Foundation (R302-2018-2155 and R155-2013-16338), the Novo Nordisk Foundation (NNF18SA0035006), the Wellcome Trust (214300), the Carlsberg Foundation (CF18-0024), the Danish National Research Foundation (DNRF94, DNRF174), the University of Copenhagen (KU2016 programme) and Ferring Pharmaceuticals A/S to E.W. This research has been conducted using the UK Biobank Resource and the iPSYCH Initiative, funded by the Lundbeck Foundation (R102-A9118 and R155-2014-1724). This work was further supported by the Swedish Foundation for Humanities and Social Sciences grant (Riksbankens Jubileumsfond M16-0455:1) to K.K. M.E.A. was supported by Marie Sk\u0142odowska-Curie Actions of the EU (grant no. 300554), The Villum Foundation (grant no. 10120) and Independent Research Fund Denmark (grant no. 7027-00147B). W.B. is supported by the Hanne and Torkel Weis-Fogh Fund (Department of Zoology, University of Cambridge). A.P. is funded by the Wellcome grant WT214300; B.S.d.M and O.D. by the Swiss National Science Foundation (SFNS PP00P3_176977) and the European Research Council (ERC 679330);.; Funding text 2: We acknowledge P. Bennike, who was involved in initiating this project, for her substantial contributions to its conception and to prehistoric research more broadly; she passed away in 2017. We thank L. Olsen and P. Selmer Olsen for administrative and technical assistance, respectively; the UK Biobank for access to the UK Biobank genomic resource; Illumina for collaboration; and S. Ellingv\u00E5g for assistance with sample access. E.W. thanks St John\u2019s College, Cambridge, for providing a stimulating environment of discussion and learning. The Lundbeck Foundation GeoGenetics Centre is supported by grants from the Lundbeck Foundation (R302-2018-2155 and R155-2013-16338), the Novo Nordisk Foundation (NNF18SA0035006), the Wellcome Trust (214300), the Carlsberg Foundation (CF18-0024), the Danish National Research Foundation (DNRF94, DNRF174), the University of Copenhagen (KU2016 programme) and Ferring Pharmaceuticals A/S to E.W. This research has been conducted using the UK Biobank Resource and the iPSYCH Initiative, funded by the Lundbeck Foundation (R102-A9118 and R155-2014-1724). This work was further supported by the Swedish Foundation for Humanities and Social Sciences grant (Riksbankens Jubileumsfond M16-0455:1) to K.K. M.E.A. was supported by Marie Sk\u0142odowska-Curie Actions of the EU (grant no. 300554), The Villum Foundation (grant no. 10120) and Independent Research Fund Denmark (grant no. 7027-00147B). W.B. is supported by the Hanne and Torkel Weis-Fogh Fund (Department of Zoology, University of Cambridge). A.P. is funded by the Wellcome grant WT214300; B.S.d.M and O.D. by the Swiss National Science Foundation (SFNS PP00P3_176977) and the European Research Council (ERC 679330); R. Macleod by an SSHRC doctoral studentship grant (G101449: \u2018Individual Life Histories in Long-Term Cultural Change\u2019); G.R. by a Novo Nordisk Foundation Fellowship (gNNF20OC0062491); N.N.J. by Aarhus University Research Foundation; B.S.P. by an ERC-Starter Grant 'NEOSEA' (grant no. 949424); H.S. by a Carlsberg Foundation Fellowship (CF19-0601); G.S. by Marie Sk\u0142odowska-Curie Individual Fellowship \u2018PALAEO-ENEO\u2019 (grant agreement number 751349); A. J. Schork by a Lundbeckfonden Fellowship (R335-2019-2318) and the National Institute on Aging (NIH award numbers U19AG023122, U24AG051129 and UH2AG064706); A.L. and I.S. by the Science Committee, Ministry of Education and Science of the Republic of Kazakhstan (AP08856317); B.G.-R. and M.G.-M. by the Spanish Ministry of Science and Innovation (project HAR2016-75605-R); C.M.-L. and O.R. by the Italian Ministry for the Universities (grants 2010-11 prot.2010EL8TXP_001, \u2018Biological and cultural heritage of the central-southern Italian population through 30 thousand years\u2019 and 2008 prot. 2008B4J2HS_001, \u2018Origin and diffusion of farming in central-southern Italy: a molecular approach\u2019); and D.C.-S. and I.G.-Z. by the Spanish Ministry of Science and Innovation (project HAR2017-86262-P). D.C.S.-G. acknowledges funding from the Generalitat Valenciana (CIDEGENT/2019/061) and the Spanish Government (EUR2020-112213). D.B. was supported by the NOMIS Foundation and Marie Sk\u0142odowska-Curie Global Fellowship 'CUSP' (grant no. 846856); E.R.U. by the Science Committee, Ministry of Education and Science of the Republic of Kazakhstan (\u0410\u042009261083: \u2018Transcultural Communications in the Late Bronze Age (Western Siberia\u2013Kazakhstan\u2013Central Asia)\u2018); E.C. by Villum Fonden (17649); J.E.A.T. by the Spanish Ministry of Economy and Competitiveness (HAR2013\u201046861\u2010R) and Generalitat Valenciana (Aico/ 2018/125 and Aico 2020/97); and P.K. by the Russian Ministry of Science and Higher Education (Ural Federal University Program of Development within the Priority-2030 Program). P.K. also acknowledges the Museum of the Institute of Plant and Animal Ecology (UB RAS, Ekaterinburg). L.Y. acknowledges funding by the Science Committee of the Armenian Ministry of Education and Science (project 21AG-1F025); L.O. by the ERC Consolidator Grant \u2018PEGASUS\u2019 (agreement no. 681605); M. Sablin by the Russian Ministry of Science and Higher Education (075-15-2021-1069); N.C. by Historic Environment Scotland; S.V. and E.V.V. by the Russian Ministry of Science and Higher Education (075-15-2022-328); and V.M. by the Science Committee, Ministry of Education and Science of the Republic of Kazakhstan (AR08856925). V.A. is supported by a Lundbeckfonden Fellowship (R335-2019-2318); P.H.S. by the National Institute of General Medical Sciences (R35GM142916); S.R. by the Novo Nordisk Foundation (NNF14CC0001); T.S.K. is funded by Carlsberg grant CF19-0712; R.D. by the Wellcome Trust (WT214300); R.N. by the National Institute of General Medical Sciences (NIH grant R01GM138634); and F. Racimo by a Villum Fonden Young Investigator Grant (no. 00025300); by a Novo Nordisk Fonden Data Science Ascending Investigator Award (NNF22OC0076816) and by the European Research Council (ERC) under the European Union\u2019s Horizon Europe programme (grant agreement No. 101077592). T.W. and V.A. are supported by the Lundbeck Foundation iPSYCH initiative (R248-2017-2003)
