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The petrography as well as the major and trace element compositions of the Selinunte grinding stones, made of grey vesicular lava, were analysed. By comparison with geochemical data from volcanic rocks in the Mediterranean, we were able to determine that only a minor number of the tools were extracted from the nearest volcanics of Mount Etna and the Hyblean Mountains, while the majority of the grinding stones were most probably imported from the Aeolian Islands, although an origin from the Aegean cannot be excluded entirely. The results are important in order to scrutinize trading connections, especially for the earlier times of settlement during the sixth century BC. [ABSTRACT FROM AUTHOR]

Massive Ca2+ influx into mitochondria is critically involved in cell death induction but it is unknown how this activates the organelle for cell destruction. Using multiple approaches including subcellular fractionation, FRET in intact cells, and in vitro reconstitutions, we show that mitochondrial Ca2+ influx prompts complex II of the respiratory chain to disintegrate, thereby releasing an enzymatically competent sub-complex that generates excessive reactive oxygen species (ROS) for cell death induction. This Ca2+-dependent dissociation of complex II is also observed in model membrane systems, but not when cardiolipin is replaced with a lipid devoid of Ca2+ binding. Cardiolipin is known to associate with complex II and upon Ca2+ binding coalesces into separate homotypic clusters. When complex II is deprived of this lipid, it disintegrates for ROS formation and cell death. Our results reveal Ca2+ binding to cardiolipin for complex II disintegration as a pivotal step for oxidative stress and cell death induction. [ABSTRACT FROM AUTHOR]

Horses revolutionized human history with fast mobility 1 . However, the timeline between their domestication and their widespread integration as a means of transport remains contentious 2-4 . Here we assemble a collection of 475 ancient horse genomes to assess the period when these animals were first reshaped by human agency in Eurasia. We find that reproductive control of the modern domestic lineage emerged around 2200 BCE, through close-kin mating and shortened generation times. Reproductive control emerged following a severe domestication bottleneck starting no earlier than approximately 2700 BCE, and coincided with a sudden expansion across Eurasia that ultimately resulted in the replacement of nearly every local horse lineage. This expansion marked the rise of widespread horse-based mobility in human history, which refutes the commonly held narrative of large horse herds accompanying the massive migration of steppe peoples across Europe around 3000 BCE and earlier 3,5 . Finally, we detect significantly shortened generation times at Botai around 3500 BCE, a settlement from central Asia associated with corrals and a subsistence economy centred on horses 6,7 . This supports local horse husbandry before the rise of modern domestic bloodlines., (© 2024. The Author(s).)

Objective: To evaluate the potential impact of the latest ESGO guidelines for endometrial cancer with molecular classification on the management strategy in a French cohort., Methods: All patients treated between January 1st, 2014 and December 31, 2020 for an endometrial cancer at the Centre Hospitalier Intercommunal de Créteil (CHIC, FRANCE) were selected from our prospectively maintained database. All postoperative samples were reviewed to confirm histological subtype, myometrial infiltration, cytonuclear grade and presence of lymphovascular emboli. Analysis of p53, MLH1, MSH2, MSH6, PMS2 genes was performed by immunohistochemistry first then a systematic POLE sequencing was performed to identify gene mutation. The impact of the latest ESGO 2020 guidelines was assessed regarding adjuvant therapy, surgical strategy, and survival., Results: Eighty patients were analyzed, including 70% NSMP (n = 56), 13.75% MSI (n = 11), 10% p53 mutated (n = 8) and 6.25% POLEmut (n = 5). A total of 21 patients (26.3%) were reclassified using the latest ESGO classification. Patients classified at low risk or with advanced / metastatic disease were not reclassified using molecular analysis. Molecular analysis and the latest ESGO classification had the most important impact on patients initially classified at intermediate - high risk that were reclassified in intermediate (10/23) and in low (4/23) risk. Nine patients (11.3%) were overtreated according to the 2020 ESGO classification: six patients in the low - risk group (4 received vaginal brachytherapy and 2 external radiotherapy) and three in the intermediate risk group (3 received external irradiation and 1 received chemotherapy). None of the patients in our cohort would have been undertreated using the 2020 ESGO classification. Patients within the p53 mutated group were the most likely to experience recurrence (37.5%, 3/8) and none of the patients POLE mutated recurred., Conclusion: Around one in 4 patients were reclassified in a more accurate prognostic group using molecular diagnosis and the latest ESGO guidelines which could decrease the use of adjuvant therapies to spare morbidity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid β in the cerebrovascular wall. The Boston criteria are used worldwide for the in-vivo diagnosis of CAA but have not been updated since 2010, before the emergence of additional MRI markers. We report an international collaborative study aiming to update and externally validate the Boston diagnostic criteria across the full spectrum of clinical CAA presentations., Methods: In this multicentre, hospital-based, retrospective, MRI and neuropathology diagnostic accuracy study, we did a retrospective analysis of clinical, radiological, and histopathological data available to sites participating in the International CAA Association to formulate updated Boston criteria and establish their diagnostic accuracy across different populations and clinical presentations. Ten North American and European academic medical centres identified patients aged 50 years and older with potential CAA-related clinical presentations (ie, spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathological assessment for CAA diagnosis. MRI scans were centrally rated at Massachusetts General Hospital (Boston, MA, USA) for haemorrhagic and non-haemorrhagic CAA markers, and brain tissue samples were rated by neuropathologists at the contributing sites. We derived the Boston criteria version 2.0 (v2.0) by selecting MRI features to optimise diagnostic specificity and sensitivity in a prespecified derivation cohort (Boston cases 1994-2012, n=159), then externally validated the criteria in a prespecified temporal validation cohort (Boston cases 2012-18, n=59) and a geographical validation cohort (non-Boston cases 2004-18; n=123), comparing accuracy of the new criteria to the currently used modified Boston criteria with histopathological assessment of CAA as the diagnostic standard. We also assessed performance of the v2.0 criteria in patients across all cohorts who had the diagnostic gold standard of brain autopsy., Findings: The study protocol was finalised on Jan 15, 2017, patient identification was completed on Dec 31, 2018, and imaging analyses were completed on Sept 30, 2019. Of 401 potentially eligible patients presenting to Massachusetts General Hospital, 218 were eligible to be included in the analysis; of 160 patient datasets from other centres, 123 were included. Using the derivation cohort, we derived provisional criteria for probable CAA requiring the presence of at least two strictly lobar haemorrhagic lesions (ie, intracerebral haemorrhages, cerebral microbleeds, or foci of cortical superficial siderosis) or at least one strictly lobar haemorrhagic lesion and at least one white matter characteristic (ie, severe visible perivascular spaces in centrum semiovale or white matter hyperintensities in a multispot pattern). The sensitivity and specificity of these criteria were 74·8% (95% CI 65·4-82·7) and 84·6% (71·9-93·1) in the derivation cohort, 92·5% (79·6-98·4) and 89·5% (66·9-98·7) in the temporal validation cohort, 80·2% (70·8-87·6) and 81·5% (61·9-93·7) in the geographical validation cohort, and 74·5% (65·4-82·4) and 95·0% (83·1-99·4) in all patients who had autopsy as the diagnostic standard. The area under the receiver operating characteristic curve (AUC) was 0·797 (0·732-0·861) in the derivation cohort, 0·910 (0·828-0·992) in the temporal validation cohort, 0·808 (0·724-0·893) in the geographical validation cohort, and 0·848 (0·794-0·901) in patients who had autopsy as the diagnostic standard. The v2.0 Boston criteria for probable CAA had superior accuracy to the current Boston criteria (sensitivity 64·5% [54·9-73·4]; specificity 95·0% [83·1-99·4]; AUC 0·798 [0·741-0854]; p=0·0005 for comparison of AUC) across all individuals who had autopsy as the diagnostic standard., Interpretation: The Boston criteria v2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their specificity in our cohorts of patients aged 50 years and older presenting with spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes. Future studies will be needed to determine generalisability of the v.2.0 criteria across the full range of patients and clinical presentations., Funding: US National Institutes of Health (R01 AG26484)., Competing Interests: Declaration of interests AC reports receiving funding from the Bodossaki Foundation and the Frechette Family Foundation and consulting fees from Imperative Care. MPF reports receiving funding from Biogen and Voyager Therapeutics. Gba reports receiving funding from the Rosetrees Trust, Alzheimer's Research UK, NIHR, and the Stroke Association. CC reports receiving funding from the French Ministry of Health and honoraria from Amgen, and participating in data safety monitoring, advisory, or steering committees for the University of Glasgow, University of Caen, Op2Lysis, AstraZeneca, Bristol Myers Squibb, and Biogen. MD reports receiving funding from Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology and the Vascular Dementia Research Foundation. JH reports receiving funding from the German Research Foundation and German Center for Neurodegenerative Diseases and tissue from Neurobiobank Munich. JL reports serving on a serving on an advisory board for Biogen and Mediaire. LP reports receiving honoraria from Daiichi Sankyo Ireland. FP reports receiving funding from the Alzheimer's Association (AARG-18-561699), participation on an Advisory Board for Roche, and leadership of the CAA Study Group of the Italia Society of Neurology-Dementia and the iCAB International Network. SR reports receiving funding from the German Research Foundation and brain tissue from Neurobiobank Munich. MAR reports receiving funding from the Wellcome Trust. JAS reports receiving funding from the US National Institutes of Health, consulting fees from Alnylam Pharmaceuticals, Apellis Pharmaceuticals, and Avid Radiopharmaceuticals, honoraria from Weil Cornell University, payment for expert testimony from the National Hockey League, support for travel from the US National Institutes for Health, serving on safety monitoring or advisory boards for the Framingham Heart Study, DISCOVERY, University of Kansas, Boston University, and University of California Irvine, and serving in leadership positions for the Alzheimer's Association and Foundation Alzheimer France. CSm reports receiving funding from the Medical Research Council UK. LS reports receiving funding from the Hungarian Academy of Sciences and Ministry for Innovation and Technology of Hungary from the source of the National Research. JMW reports receiving funding from the UK Dementia Research Institute funded by the UK Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK, and a leadership role for the European Stroke Organization SVD Guidelines. FAW reports receiving honoraria from Alexion Pharm. MEG reports receiving funding from Avid Radiopharmaceuticals, Pfizer, and Boston Scientific. AV reports receiving funding from the US National Institutes of Health and consulting fees from Alnylam Pharmaceuticals and Biogen Pharmaceuticals. RA-SS reports receiving funding from the UK Medical Research Council and the Stroke Association. EES reports receiving funding from the Canadian Institutes of Health Research, Brain Canada, and Biogen, and consulting fees from Biogen and Eli Lily. DJW reports receiving consulting fees from Alnylam and Novo Nordisk, honoraria from Bayer and Alexion, participation on a safety monitoring board for the OXHARP study, and serving in leadership for the British Association of Stroke Physicians. SMG reports receiving funding from the US National Institutes of Health, royalties from Up-To-Date, consulting fees from Eli Lily, and serving on data safety monitoring committees for Washington University, Bayer, Biogen, and Roche. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Diagnosing probable cerebral amyloid angiopathy (CAA) after lobar intra-cerebral hemorrhage (l-ICH) currently relies on the MR-based modified Boston criteria (mBC). However, MRI has limited availability and the mBC have moderate sensitivity, with isolated l-ICH being classified as "possible CAA". A recent autopsy-based study reported potential value of finger-like projections (FLP) and subarachnoid hemorrhage (SAH) on acute CT. Here we assessed these markers' performance in a cohort most of whom survived the index episode., Methods: We included all patients from a prospective pathology database with non-traumatic l-ICH, admission CT and available tissue sample showing no alternative cause. CT was assessed by two blinded independent neuroradiologists. Interobserver reproducibility was almost perfect for SAH and substantial for FLP., Results: Sixteen patients were eligible [age 65.8 ± 7.2 yrs; hematoma volume: 39(26, 71)mls; hematoma evacuation sample 15 patients; autopsy one patient]. MRI was available in 11 patients. ICH-related death affected six patients. Aβ 40-42 immunohistochemistry revealed CAA in seven patients (44%). SAH and FLP were present in 12/16 (75%) and 10/16 (62%) patients, respectively. SAH had 100% sensitivity for CAA but low specificity; FLP had lower performance. Using either pathology or MRI as reference standard yielded essentially similar results. All patients with possible CAA on MRI but CAA on pathology had SAH., Conclusions: In patients with moderate-size l-ICH who mostly survived the index event, SAH had perfect sensitivity and better performance than FLP. In addition, SAH appeared to add onto MRI in possible CAA, the clinically most relevant scenario. Studies in larger samples are however warranted., (© 2021. The Author(s).)

Domestication of horses fundamentally transformed long-range mobility and warfare 1 . However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling 2-4 at Botai, Central Asia around 3500 BC 3 . Other longstanding candidate regions for horse domestication, such as Iberia 5 and Anatolia 6 , have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 BC, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the GSDMC and ZFPM1 genes. Our results reject the commonly held association 7 between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 BC 8,9 driving the spread of Indo-European languages 10 . This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium BC Sintashta culture 11,12 ., (© 2021. The Author(s).)

Gene expression can be noisy, as can the growth of single cells. Such cell-to-cell variation has been implicated in survival strategies for bacterial populations. However, it remains unclear how single cells couple gene expression with growth to implement these strategies. Here, we show how noisy expression of a key stress-response regulator, RpoS, allows E. coli to modulate its growth dynamics to survive future adverse environments. We reveal a dynamic positive feedback loop between RpoS and growth rate that produces multi-generation RpoS pulses. We do so experimentally using single-cell, time-lapse microscopy and microfluidics and theoretically with a stochastic model. Next, we demonstrate that E. coli prepares for sudden stress by entering prolonged periods of slow growth mediated by RpoS. This dynamic phenotype is captured by the RpoS-growth feedback model. Our synthesis of noisy gene expression, growth, and survival paves the way for further exploration of functional phenotypic variability.

Self-assembly of the amphiphilic π-conjugated carbenium ion ATOTA-1(+) in aqueous solution selectively leads to discrete and highly stable nanotubes or nanoribbons and nanorods, depending on the nature of the counterion (Cl(-) vs. PF6(-), respectively). The nanotubes formed by the Cl(-) salt illustrate an exceptional example of a structural well-defined (29±2 nm in outer diameter) unilamellar tubular morphology featuring π-conjugated functionality and high stability and flexibility, in aqueous solution., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)