Enhanced phosphorus weathering contributed to Late Miocene cooling.

Late Miocene climate evolution provides an opportunity to assess Earth's climate sensitivity to carbon cycle perturbation under warmer-than-modern conditions. Despite its relevance for understanding the climate system, the driving mechanisms underlying profound climate and carbon cycle changes - including the enigmatic Late Miocene cooling from 7 to 5.4 million years ago - remain unclear.

A catalogue of land-based adaptation and mitigation solutions to tackle climate change.

Informing and engaging all actors in the land sector, including land-owners and managers, researchers, policy-makers and citizens, on the most effective sustainable land-based solutions and behavioural changes is a key strategy for achieving climate change adaptation and mitigation targets at the global as well as at EU and local level. One requisite to support actors in the land sector is to provide them publicly available, reliable and ready-to-use information related to the implementation of Land-based Adaptation and Mitigation Solutions (LAMS). Here we introduce a LAMS catalogue, a collection of meaningful quantitative and qualitative information on 60 solutions characterised according to a set of specifications (e.

PARP inhibition-associated heterochromatin confers increased DNA replication stress and vulnerability to ATR inhibition in SMARCA4-deficient cells.

DNA replication stress (RS), a prevalent feature of various malignancies, arises from both genetic mutations and genotoxic exposure. Elevated RS levels increase the vulnerability of cancer cells to ataxia telangiectasia and Rad3-related kinase inhibitors (ATRis). Here, we screened for DNA damage response inhibitors that enhance ATRi-induced cytotoxicity using SWI/SNF complex-deficient cells and identified a potent synergy between ATRi and poly(ADP-ribose) polymerase inhibitor (PARPi), particularly in SMARCA4-deficient cells.

Molecular Insights into α-Synuclein Fibrillation: A Raman Spectroscopy and Machine Learning Approach.

The aggregation of α-synuclein is crucial to the development of Lewy body diseases, including Parkinson's disease and dementia with Lewy bodies. The aggregation pathway of α-synuclein typically involves a defined sequence of nucleation, elongation, and secondary nucleation, exhibiting prion-like spreading. This study employed Raman spectroscopy and machine learning analysis, alongside complementary techniques, to characterize the biomolecular changes during the fibrillation of purified recombinant wild-type α-synuclein protein.

Overcoming the technical challenge of venous resection with pancreatectomy: Which factors determine survival?

Background: Pancreatectomy with venous resection (PVR) is nowadays considered standard. However, there is still concern about increased postoperative morbidity and impaired long-term outcome depending on the type of venous resection and reconstruction. The aim was to investigate the predictors of morbidity and long-term survival in patients undergoing PVR in a high-volume center.

Skeletal Editing through Cycloaddition and Subsequent Cycloreversion Reactions.

ConspectusSkeletal editing, which involves adding, deleting, or substituting single or multiple atoms within ring systems, has emerged as a transformative approach in modern synthetic chemistry. This innovative strategy addresses the ever-present demand for developing new drugs and advanced materials by enabling precise modifications of molecular frameworks without disrupting essential functional complexities. Ideally performed at late stages of synthesis, skeletal editing minimizes the need for the cost- and labor-intensive processes often associated with synthesis, thus accelerating the discovery and optimization of complex molecular architectures.

[Bimodal and multimodal endoscopy of the urinary bladder in diagnosis and treatment].

White light cystoscopy is a precise instrument for the detection and treatment of papillary bladder tumors. Various additional macroscopic detection methods have been established. Some of them, especially PDD or NBI, have been shown to have an additional benefit on the recurrence rate of bladder tumors, so they should be used as part of the diagnosis and treatment when available.

Visual and Orthoptic Development After DSAEK for CHED in Children Younger than 8 years: Case Series and Literature Review.

Purpose: Congenital hereditary endothelial dystrophy (CHED) impairs the sensitive phase of visual development. We examined results of Descemet stripping automated endothelial keratoplasty (DSAEK) for CHED regarding the critical period for amblyogenic factors.

Methods: Retrospective analysis of 11 eyes of 6 consecutive patients with CHED younger than 8 years treated with DSAEK and a PubMed-based literature search on management and optimal timing of the intervention.

Trace elements increase replicability of microbial growth.

Trace elements are often omitted from chemically defined growth media. From established properties of trace elements, we deduce that this omission makes experiments unnecessarily sensitive to unavoidable contamination with trace elements. We confirm this experimentally by growing 11 bacterial strains in high replicate with and without supplementing trace elements, keeping all other conditions as fixed as possible to isolate the effect of trace elements.

Formulation screening of lyophilized mRNA-lipid nanoparticles.

Lipid nanoparticles (LNPs) have demonstrated their therapeutic potential as safe and effective drug delivery systems for nucleic acids during the COVID-19 pandemic. However, one of the main challenges during technical CMC (Chemistry, Manufacturing, and Controls) development is their long-term stability at temperatures of 2-8 °C or higher, which may be improved by the removal of water by lyophilization. In this study, we identified lyo-/cryo-protectants for freeze-dried mRNA-LNP formulations beyond conventional excipients such as sucrose and trehalose as T-modifiers using polyA as a surrogate.

A comprehensive report of the clinical and mutational profiles of 30 Iranian malignant infantile osteopetrosis patients.

Osteopetrosis is a group of genetically and clinically diverse inherited disorders characterized by an increase in bone density. The main known cause is an abnormality in the development or function of osteoclasts. Hence, the process of bone resorption is impaired, resulting in: 1- a reduction in bone marrow volume and, subsequently, a decrement in the hematopoietic capacity of bone marrow, which leads to anemia and compromised immunological function; 2- improper bone development, which leads to pressure on peripheral nerves, causing auditory, visual, and movement impairments; and 3- disturbance in the formation of bone microstructure that leads to susceptibility to bone fracture.

Investigating the Multigenerational Effects of DDT Residues Exposure on Dental Development in Wistar Rats.

The pesticide Dichlorodiphenyltrichloroethane (DDT) and its degradation by-products (Dichlorodiphenyldichloroethane-DDD and dichlorodiphenyldichloroethylene-DDE) are health concerns. This study aimed to investigate the impact of multigenerational exposure to traces of DDD and DDE on odontogenesis Wistar rats were allocated in 4 groups over 2 generations (F1 and F2). Water was provided ad libitum throughout the animal's life groups: control - natural water; DDD - 0.

Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial.

Background: CheckMate 8HW prespecified dual primary endpoints, assessed in patients with centrally confirmed microsatellite instability-high or mismatch repair-deficient status: progression-free survival with nivolumab plus ipilimumab compared with chemotherapy as first-line therapy and progression-free survival with nivolumab plus ipilimumab compared with nivolumab alone, regardless of previous systemic treatment for metastatic disease. In our previous report, nivolumab plus ipilimumab showed superior progression-free survival versus chemotherapy in first-line microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer in the CheckMate 8HW trial. Here, we report results from the prespecified interim analysis for the other primary endpoint of progression-free survival for nivolumab plus ipilimumab versus nivolumab across all treatment lines.

VAE-Surv: A novel approach for genetic-based clustering and prognosis prediction in myelodysplastic syndromes.

Background And Objectives: Several computational pipelines for biomedical data have been proposed to stratify patients and to predict their prognosis through survival analysis. However, these analyses are usually performed independently, without integrating the information derived from each of them. Clustering of survival data is an underexplored problem, and current approaches are limited for biomedical applications, whose data are usually heterogeneous and multimodal, with poor scalability for high-dimensionality.

Clinical outcomes and management following progressive disease with anti-PD-(L)1 therapy in patients with advanced Merkel Cell Carcinoma.

Aim: Merkel Cell Carcinoma (MCC) is a rare skin cancer with a rising incidence worldwide. Anti-programmed death-1/ligand-1 (anti-PD-(L)1) therapies are effective for the treatment of advanced MCC. This study examines patterns of response / progression of advanced MCC to anti-PD-(L)1 therapies and describes subsequent management.

Cancer-specific utility instrument for health economic evaluations: A synopsis of the EORTC QLU-C10D user manual and current validity evidence.

The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Utility - Core 10 Dimensions (QLU-C10D) adds a preference-based scoring algorithm to the EORTC measurement portfolio. It is built on the most widely used health-related quality of life (HRQoL) measure in oncology, the EORTC Quality of Life Questionnaire - Core 30 (QLQ-C30), allowing for the calculation of both HRQoL profiles and health utilities. This is an important advancement for integrating cancer-specific values into health economic evaluations and decision making, offering greater content validity and statistical power than some generic measures.

Freshwater browning as a hidden threat - Transcriptomic responses in fish gills exposed to fulvic acid.

Human activities and climate change have significantly increased humic substances in freshwater ecosystems over the last few decades. This increase is particularly concerning during seasonal changes or after heavy rainfall, when concentrations can easily increase up to tenfold. This phenomenon, known as "browning," has unknown consequences for aquatic organisms.

What makes a trauma 'pathological'? - Perceived peritraumatic threat influences the development of intrusive memories.

Intrusions are a hallmark symptom of posttraumatic stress disorder (PTSD). While dysfunctional cognitions are known posttraumatic contributors, peritraumatic processes are less understood. Perceived threat, alongside emotional factors, is theorized as significant, but experimental studies are lacking.

Elucidating therapist differences: Therapists' interpersonal skills and their effect on treatment outcome.

Objective: Therapists differ in their average treatment outcomes. However, it remains unclear which characteristics differentiate more from less effective therapists. This study examined the association between therapist interpersonal skills and treatment outcome as well as the moderating effect of initial impairment.

The cost of fear: Impairments of decision-making in specific phobia.

Background: Decision-making processes may play a pivotal role in the etiology and maintenance of specific phobia. However, empirical evidence is limited. This study examined whether decision-making is only impaired in presence of fear-related stimuli or whether general impairments exist but are more pronounced in the presence of fear-related stimuli.

Oil palm smallholders and the road to certification: Insights from Indonesia.

Smallholder-managed oil palm plantations are a major driver of economic welfare and rural development. However, compared to industrial producers, smallholders are associated with lower farm productivity and disproportionately higher rates of illegal land clearing. Therefore, a balance must be struck between mitigating adverse externalities and strengthening favorable outcomes to ensure smallholders' sustainable integration into the palm oil industry.

Steatohepatitis-induced vascular niche alterations promote melanoma metastasis.

Background: In malignant melanoma, liver metastases significantly reduce survival, even despite highly effective new therapies. Given the increase in metabolic liver diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), this study investigated the impact of liver sinusoidal endothelial cell (LSEC)-specific alterations in MASLD/MASH on hepatic melanoma metastasis.

Methods: Mice were fed a choline-deficient L-amino acid-defined (CDAA) diet for ten weeks to induce MASH-associated liver fibrosis, or a CDAA diet or a high fat diet (HFD) for shorter periods of time to induce early steatosis-associated alterations.

Biphasic lipid extraction from microalgae after PEF-treatment reduces the energy demand of the downstream process.

Background: The gradual extrusion of water-soluble intracellular components (such as proteins) from microalgae after pulsed electric field (PEF) treatment is a well-documented phenomenon. This could be utilized in biorefinery applications with lipid extraction taking place after such an 'incubation' period, i.e.

NPT100-18A rescues mitochondrial oxidative stress and neuronal degeneration in human iPSC-based Parkinson's model.

Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by protein aggregates mostly consisting of misfolded alpha-synuclein (αSyn). Progressive degeneration of midbrain dopaminergic neurons (mDANs) and nigrostriatal projections results in severe motor symptoms. While the preferential loss of mDANs has not been fully understood yet, the cell type-specific vulnerability has been linked to a unique intracellular milieu, influenced by dopamine metabolism, high demand for mitochondrial activity, and increased level of oxidative stress (OS).

Time-resolved momentum microscopy with fs-XUV photons at high repetition rates with flexible energy and time resolution.

Time-resolved momentum microscopy is an emerging technique based on photoelectron spectroscopy for characterizing ultrafast electron dynamics and the out-of-equilibrium electronic structure of materials in the entire Brillouin zone with high efficiency. In this article, we introduce a setup for time-resolved momentum microscopy based on an energy-filtered momentum microscope coupled to a custom-made high-harmonic generation photon source driven by a multi-100 kHz commercial Yb-ultrafast laser that delivers fs pulses in the extreme ultraviolet range. The laser setup includes a nonlinear pulse compression stage employing spectral broadening in a Herriott-type bulk-based multi-pass cell.