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Accelerator mass spectrometry radiocarbon dating is used to construct a chronology of Neanderthal disappearance, showing that Neanderthals overlapped with anatomically modern humans for between about 2,000 and 5,000 years. Gradual displacement of Neanderthals Did anatomically modern humans coexist with Neanderthals? Attempts to answer this question are complicated by the fact that conventional methods of radiocarbon dating become unreliable at just about the time in question: as sample ages approach 50,000 years little carbon-14 is left and it is difficult to obtain accurate measurements. Tom Higham and colleagues have worked to improve sample processing and accelerator-mass-spectrometry radiocarbon dating in order to construct a robust chronology based on the last appearances of the Mousterian tool culture — considered diagnostic for the presence of Neanderthals — from forty sites from Spain to Russia. The results indicate that Neanderthals disappeared at different times in different regions, with a significant overlap with incoming modern humans for around 2,600 to 5,400 years. Rather than a rapid model of replacement, this work suggests a complex picture in which cultural and biological interchange could have occurred between the two groups across a period of several thousand years. The timing of Neanderthal disappearance and the extent to which they overlapped with the earliest incoming anatomically modern humans (AMHs) in Eurasia are key questions in palaeoanthropology 1 , 2 . Determining the spatiotemporal relationship between the two populations is crucial if we are to understand the processes, timing and reasons leading to the disappearance of Neanderthals and the likelihood of cultural and genetic exchange. Serious technical challenges, however, have hindered reliable dating of the period, as the radiocarbon method reaches its limit at ∼50,000 years ago 3 . Here we apply improved accelerator mass spectrometry 14 C techniques to construct robust chronologies from 40 key Mousterian and Neanderthal archaeological sites, ranging from Russia to Spain. Bayesian age modelling was used to generate probability distribution functions to determine the latest appearance date. We show that the Mousterian ended by 41,030–39,260 calibrated years bp (at 95.4% probability) across Europe. We also demonstrate that succeeding ‘transitional’ archaeological industries, one of which has been linked with Neanderthals (Châtelperronian) 4 , end at a similar time. Our data indicate that the disappearance of Neanderthals occurred at different times in different regions. Comparing the data with results obtained from the earliest dated AMH sites in Europe, associated with the Uluzzian technocomplex 5 , allows us to quantify the temporal overlap between the two human groups. The results reveal a significant overlap of 2,600–5,400 years (at 95.4% probability). This has important implications for models seeking to explain the cultural, technological and biological elements involved in the replacement of Neanderthals by AMHs. A mosaic of populations in Europe during the Middle to Upper Palaeolithic transition suggests that there was ample time for the transmission of cultural and symbolic behaviours, as well as possible genetic exchanges, between the two groups.

Selective KRAS G12C inhibitors have been developed to covalently lock the oncogene in the inactive GDP-bound state. Two of these molecules, sotorasib and adagrasib, are approved for the treatment of adult patients with KRAS G12C -mutated previously treated advanced non-small cell lung cancer. Drug treatment imposes selective pressures leading to the outgrowth of drug-resistant variants. Mass sequencing from patients’ biopsies identified a number of acquired KRAS mutations -both in cis and in trans - in resistant tumors. We demonstrate here that disease progression in vivo can also occur due to adaptive mechanisms and increased KRAS-GTP loading. Using the preclinical tool tri-complex KRAS G12C -selective covalent inhibitor, RMC-4998 (also known as RM-029), that targets the active GTP-bound (ON) state of the oncogene, we provide a proof-of-concept that the clinical stage KRAS G12C (ON) inhibitor RMC-6291 alone or in combination with KRAS G12C (OFF) drugs can be an alternative potential therapeutic strategy to circumvent resistance due to increased KRAS-GTP loading. KRAS G12C mutant selective inhibitors targeting inactive state have been approved for use in non-small cell lung cancer (NSCLC). Here, using models derived from a patient with NSCLC who progressed on sotorasib (KRAS G12C inhibitor), the authors identify increased KRAS GTP loading as an adaptive resistance mechanism which could be targeted with KRAS G12C inhibitors selective to the GTP active state.

Transcriptional profiling of Kras -driven early lesions—aimed at identifying founder events—reveals DDR1 as a therapeutic target relevant to adenocarcinoma. Patients with advanced Kirsten rat sarcoma viral oncogene homolog ( KRAS )-mutant lung adenocarcinoma are currently treated with standard chemotherapy because of a lack of efficacious targeted therapies. We reasoned that the identification of mediators of Kras signaling in early mouse lung hyperplasias might bypass the difficulties that are imposed by intratumor heterogeneity in advanced tumors, and that it might unveil relevant therapeutic targets. Transcriptional profiling of Kras G12V -driven mouse hyperplasias revealed intertumor diversity with a subset that exhibited an aggressive transcriptional profile analogous to that of advanced human adenocarcinomas. The top-scoring gene in this profile encodes the tyrosine kinase receptor DDR1. The genetic and pharmacological inhibition of DDR1 blocked tumor initiation and tumor progression, respectively. The concomitant inhibition of both DDR1 and Notch signaling induced the regression of KRAS ; TP53 -mutant patient-derived lung xenografts (PDX) with a therapeutic efficacy that was at least comparable to that of standard chemotherapy. Our data indicate that the combined inhibition of DDR1 and Notch signaling could be an effective targeted therapy for patients with KRAS -mutant lung adenocarcinoma.

Mutations in the RAS–RAF–MEK–ERK pathway are frequent alterations in cancer and RASopathies, and while RAS oncogene activation alone affects 19% of all patients and accounts for approximately 3.4 million new cases every year, less frequent alterations in the cascade's downstream effectors are also involved in cancer etiology. RAS proteins initiate the signaling cascade by promoting the dimerization of RAF kinases, which can act as oncoproteins as well: BRAFV600E is the most common oncogenic driver, mutated in the 8% of all malignancies. Research in this field led to the development of drugs that target the BRAFV600‐like mutations (Class I), which are now utilized in clinics, but cause paradoxical activation of the pathway and resistance development. Furthermore, they are ineffective against non‐BRAFV600E malignancies that dimerize and could be either RTK/RAS independent or dependent (Class II and III, respectively), which are still lacking an effective treatment. This review discusses the recent advances in anti‐RAF therapies, including paradox breakers, dimer‐inhibitors, immunotherapies, and other novel approaches, critically evaluating their efficacy in overcoming the therapeutic limitations, and their putative role in blocking the RAS pathway. RAS proteins initiate the RAS–RAF–MEK–ERK signaling by promoting dimerization of RAF kinases, also active as oncoproteins. Drugs targeting BRAFV600‐like mutations (Class I) cause the paradoxical effect and resistance, and are ineffective against other classes of BRAF malignancies. This review explores recent advances in anti‐RAF therapies, including paradox breakers, dimer‐inhibitors, and immunotherapies, assessing their efficacy in overcoming therapeutic limitations and potential roles in blocking the RAS pathway.

Corporate sustainability reports’ credibility of environmental, social, and governance (ESG) information has received a significant focus of attention in the businesses landscape. Over the last years, various methodologies and multicriteria approaches have been developed to assess the ESG performance of companies. To consider the uncertainty that arises from imprecision and subjectivity in evaluating ESG criteria, this paper proposes to develop a novel hybrid methodology that combines AHP and TOPSIS techniques under a neutrosophic environment. We test the suggested proposal through a real case study of the leading companies in the oil and gas industry. Moreover, we conduct a sensitivity analysis for evaluating any discrepancies in the ranking due to using different fuzzy numbers and weighting vectors. First published online 05 July 2022

The KRAS oncoprotein is a frequent tumor driver in lung, pancreatic, and colorectal cancers and has proven to be a challenging pharmaceutical target. The first KRAS‐targeted therapeutics are now being tested in clinical trials but the consequences of preferentially targeting the GDP or GTP state of KRAS and the relevance of RAS nanoclustering have remained unclear. Here we report a Designed Ankyrin Repeat Protein (DARPin) that recognizes the RAS switch I/II region with low nm affinity, independently of the nucleotide bound (GDP‐ or GTP state). This DARPin, termed ‘784_F5’, occupies the effector recognition lobe, resulting in interference with SOS‐mediated activation, RAS downstream effector interactions, and KRAS nanoclustering. Consequently, this anti‐RAS DARPin potently blocks downstream signaling, leading to a strong reduction in proliferation and anchorage‐independent growth in RAS‐dependent cell lines. We showed that the expression of ‘784_F5’, the pan‐RAS, nucleotide‐independent DARPin can lead to tumor regression in a colorectal xenograft model which may hold promise for further investigation and development. We report a Designed Ankyrin Repeat Protein that binds and inhibits RAS proteins, which serve as central cell signaling hubs and are essential for the progression of many cancers. Its unique feature is that it does not discriminate between different RAS isoforms or mutations and is capable of binding to RAS in both its active (GTP‐bound) and inactive (GDP‐bound) states.

Specific reactive oxygen species activate the GTPase Kirsten rat sarcoma virus (KRAS) by reacting with cysteine 118 (C118), leading to an electron transfer between C118 and nucleoside guanosine diphosphate (GDP), which causes the release of GDP. Here, we have mimicked permanent oxidation of human KRAS at C118 by replacing C118 with aspartic acid (C118D) in KRAS to show that oncogenic mutant KRAS is selectively inhibited via oxidation at C118, both in vitro and in vivo. Moreover, the combined treatment of hydrogen‐peroxide‐producing pro‐oxidant paraquat and nitric‐oxide‐producing inhibitor N(ω)‐nitro‐l‐arginine methyl ester selectively inhibits human mutant KRAS activity by inducing oxidization at C118. Our study shows for the first time the vulnerability of human mutant KRAS to oxidation, thereby paving the way to explore oxidation‐based anti‐KRAS treatments in humans. Oncogenic mutant Kirsten rat sarcoma virus (KRAS) is one of the major drivers of human cancer, making it a key target in the fight against the disease. This study discovered a novel mechanism to selectively inhibit oncogenic human mutant KRAS through oxidation at cysteine 118. This finding opens new avenues for exploring potential oxidation‐based anti‐KRAS treatments in humans. The PyMOL Molecular Graphics System, Version 3.0.4, Schrödinger, LLC has been used to generate KRAS model.

In light of the emphasis on innovation as a driver of economic growth, new tools are needed to measure and compare national innovation systems. Improving methodological approaches to constructing composite innovation indicators also requires exploring issues related to aggregation, weighting, and reviewing the quality and validity of the data. This paper aims to support this debate by assessing the process and outcomes of innovation using fuzzy theory combined with a multicriteria technique to address the uncertainty attached to the underlying data used in constructing the composite indicator. Mainly, we deal with the problems related to the uniformity of the period covered by the indicator and the origin and reliability of the source of information by incorporating degrees of truth, indeterminacy, and falsity into the assessment process by applying neutrosophic numbers. To test the effectiveness of our approach, an empirical analysis is carried out based on the European Innovation Scoreboard and the assessment of the elementary criteria over the period 2020–2023.

BRAF and MEK inhibitors (BRAF/MEKi) have radically changed the treatment landscape of advanced BRAF mutation-positive tumours. However, limited efficacy and emergence of drug resistance are major barriers for successful treatments. Here, by using relevant preclinical models, we find that Connexin43 (Cx43), a protein that plays a role in cell-to-cell communication, enhances the effectiveness of BRAF/MEKi by recruiting DNA repair complexes to lamin-associated domains and promoting persistent DNA damage and cellular senescence. The nuclear compartmentalization promoted by Cx43 contributes to genome instability and synthetic lethality caused by excessive DNA damage, which could provide a therapeutic approach for these tumours to overcome drug resistance. Based on these findings, we designed a drug combination using small extracellular vesicles (sEVs) to deliver the full-Cx43 in combination with the BRAF/MEKi. This study reveals Cx43 as a regulator of DNA repair and BRAF/MEKi response, highlighting the therapeutic potential that this approach could eventually have in the clinic to overcome the limitations of current therapies and improve treatment outcomes for patients with advanced BRAF mutant tumours. Drug resistance remains a major challenge in cancer treatment. Here, the authors identify Connexin43 as target that enhances BRAF/MEKi efficacy by interfering with DNA repair pathways, overcoming drug resistance. They develop an mRNA therapy that improves efficacy and sensitizes resistant cells.

Fuzzy analytic hierarchy process (FAHP) methodologies have witnessed a growing development from the late 1980s until now, and countless FAHP based applications have been published in many fields including economics, finance, environment or engineering. In this context, the FAHP methodologies have been generally restricted to fuzzy numbers with linear type of membership functions (triangular numbers—TN—and trapezoidal numbers—TrN). This paper proposes an extended FAHP model (E-FAHP) where pairwise fuzzy comparison matrices are represented by a special type of fuzzy numbers referred to as (m,n)-trapezoidal numbers (TrN (m,n)) with nonlinear membership functions. It is then demonstrated that there are a significant number of FAHP approaches that can be reduced to the proposed E-FAHP structure. A comparative analysis of E-FAHP and Mikhailov’s model is illustrated with a case study showing that E-FAHP includes linear and nonlinear fuzzy numbers.