Personalized, autologous neoantigen-specific T cell therapy in metastatic melanoma: a phase 1 trial.

New treatment approaches are warranted for patients with advanced melanoma refractory to immune checkpoint blockade (ICB) or BRAF-targeted therapy. We designed BNT221, a personalized, neoantigen-specific autologous T cell product derived from peripheral blood, and tested this in a 3 + 3 dose-finding study with two dose levels (DLs) in patients with locally advanced or metastatic melanoma, disease progression after ICB, measurable disease (Response Evaluation Criteria in Solid Tumors version 1.1) and, where appropriate, BRAF-targeted therapy.

Clinicogenomic landscape of pancreatic adenocarcinoma identifies KRAS mutant dosage as prognostic of overall survival.

Nearly all pancreatic adenocarcinomas (PDAC) are genomically characterized by KRAS exon 2 mutations. Most patients with PDAC present with advanced disease and are treated with cytotoxic therapy. Genomic biomarkers prognostic of disease outcomes have been challenging to identify.

Establishing bio-logging data collections as dynamic archives of animal life on Earth.

Rapid growth in bio-logging-the use of animal-borne electronic tags to document the movements, behaviour, physiology and environments of wildlife-offers opportunities to mitigate biodiversity threats and expand digital natural history archives. Here we present a vision to achieve such benefits by accounting for the heterogeneity inherent to bio-logging data and the concerns of those who collect and use them. First, we can enable data integration through standard vocabularies, transfer protocols and aggregation protocols, and drive their wide adoption.

AND-gated protease-activated nanosensors for programmable detection of anti-tumour immunity.

The forward design of biosensors that implement Boolean logic to improve detection precision primarily relies on programming genetic components to control transcriptional responses. However, cell- and gene-free nanomaterials programmed with logical functions may present lower barriers for clinical translation. Here we report the design of activity-based nanosensors that implement AND-gate logic without genetic parts via bi-labile cyclic peptides.

Prevalence of lipophilic phycotoxins with different forms in the benthic environments of a typical mariculture bay.

Lipophilic phycotoxins (LPTs) are toxic and lipophilic secondary metabolites produced by toxic microalgae, which pose a serious threat to marine shellfish culture industries. LPTs were systematically investigated in bottom seawater, suspended particulate matter (SPM), sediment, and sediment porewater of Laizhou Bay, a typical mariculture bay in China, to understand the chemical diversity and environment behaviors of LPTs in the benthic environments. Okadaic acid (OA), pectenotoxin-2 (PTX2), dinophysistoxin-1 (DTX1), azaspiracid-2 (AZA2), gymnodimine (GYM), pectenotoxin-2 seco acid (PTX2 SA), 7-epi- pectenotoxin-2 seco acid (7-epi-PTX2 SA), 13-desmethylspirolide C (SPX1), yessotoxin (YTX) and homo YTX (h-YTX) were detected in the benthic environment of Laizhou Bay in spring, indicating that LPTs are rich in chemical diversity.

Nudges for people who think.

The naiveté of the dominant 'cognitive-miser' metaphor of human thinking hampers theoretical progress in understanding how and why subtle behavioural interventions-'nudges'-could work. We propose a reconceptualization that places the balance in agency between, and the alignment of representations held by, people and choice architects as central to determining the prospect of observing behaviour change. We argue that two aspects of representational (mis)alignment are relevant: cognitive (how people construe the factual structure of a decision environment) and motivational (the importance of a choice to an individual).

Transcriptional coupling of telomeric retrotransposons with the cell cycle.

Unlike most species that use telomerase for telomere maintenance, many dipterans, including , rely on three telomere-specific retrotransposons (TRs)-, , and -to form tandem repeats at chromosome ends. Although TR transcription is crucial in their life cycle, its regulation remains poorly understood. This study identifies the Mediator complex, E2F1-Dp, and Scalloped/dTEAD as key regulators of TR transcription.

How does dopamine convert into norepinephrine? Insights on the key step of the reaction.

Context: Dopamine -monooxygenase (D M) is an essential enzyme in the organism that regioselectively converts dopamine into R-norepinephrine, the key step of the reaction, studied in this paper, is a hydrogen atom transfer (HAT) from dopamine to a superoxo complex on D M, forming a hydroperoxo intermediate and dopamine radical. It was found that the formation of a hydrogen bond between dopamine and the D M catalyst strengthens the substrate-enzyme interaction and facilitates the HAT which takes place selectively to give the desired enantiomeric form of the product. Six reactions leading to the hydroperoxo intermediate were analyzed in detail using theoretical and computational tools in order to identify the most probable reaction mechanism.

Experimental and computational kinetic evaluations of silver(I)-catalyzed oxidation of -chlorophenol by hexacyanoferrate(III): exploring the mechanistic pathway.

The present investigation delves into the redox reaction between -chlorophenol (-CP) and hexacyanoferrate(III) [HCF(III)], catalyzed by Ag(I) in an alkaline environment. Findings reveal a first-order dependence on both -CP and the oxidant, and the reaction rate showcased a first-order reaction towards Ag(I), which was further amplified by the medium as per the equation = + [OH]. Interestingly, the ionic strength remained unchanged throughout the reaction, exerting no discernible effect on the reaction rate.

Dense Paraphrasing for multimodal dialogue interpretation.

Multimodal dialogue involving multiple participants presents complex computational challenges, primarily due to the rich interplay of diverse communicative modalities including speech, gesture, action, and gaze. These modalities interact in complex ways that traditional dialogue systems often struggle to accurately track and interpret. To address these challenges, we extend the textual enrichment strategy of Dense Paraphrasing (DP), by translating each nonverbal modality into linguistic expressions.

The uropathologist of the future: getting ready with intelligence for the prostate cancer tsunami.

According to the recently published paper by the Lancet Commission on prostate cancer (PCa) , the projections of new cases of PCa will rise from 1.4 million in 2020 to 2.9 million by 2040.

A Low-Cost, Open-Source 3D Printer for Multimaterial and High-Throughput Direct Ink Writing of Soft and Living Materials.

Direct ink writing is a 3D printing method that is compatible with a wide range of structural, elastomeric, electronic, and living materials, and it continues to expand its uses into physics, engineering, and biology laboratories. However, the large footprint, closed hardware and software ecosystems, and expense of commercial systems often hamper widespread adoption. This work introduces a compact, low-cost, multimaterial, and high-throughput direct ink writing 3D printer platform with detailed assembly files and instructions provided freely online.

A Lactobacillus consortium provides insights into the sleep-exercise-microbiome nexus in proof of concept studies of elite athletes and in the general population.

Background: The complex relationship among sleep, exercise, and the gut microbiome presents a unique opportunity to improve health and wellness. Here, we conducted the first large-scale investigation into the influence of a novel elite athlete-derived probiotic, consisting of a multi-strain Lactobacillus consortium, on sleep quality, exercise recovery, and gut microbiome composition in both elite athletes (n = 11) and the general population (n = 257).

Results: Our two-phase study design, which included an open-label study followed by a controlled longitudinal study in a professional soccer team, allowed us to identify key interactions between probiotics, the gut microbiome, and the host.

The β Common Cytokine Receptor Family Reveals New Functional Paradigms From Structural Complexities.

Cytokines are small proteins that are critical for controlling the growth and activity of hematopoietic cells by binding to cell surface receptors and transmitting signals across membranes. The β common (βc) cytokine receptor family, consisting of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 cytokine receptors, is an architype of the heterodimeric cytokine receptor systems. We now know that signaling by cytokine receptors is not always an "all or none" phenomenon.

The genomic secrets of invasive plants.

Genomics has revolutionised the study of invasive species, allowing evolutionary biologists to dissect mechanisms of invasion in unprecedented detail. Botanical research has played an important role in these advances, driving much of what we currently know about key determinants of invasion success (e.g.

A novel electrochemical sensor for the determination of cadmium ions based on nitrogen-enriched carbon modified electrode.

In the present work, nitrogen-doped carbon was synthesized starting from a chitosan/urea mixture and immobilized at the surface of a bare glassy carbon electrode to detect Cd(II) ions using differential pulse-anodic stripping voltammetry method (DP-ASV). The synthesized nitrogen-doped carbon showed a significant potential for determining Cd(II) ions. Doping carbon with nitrogen atoms gives a structure with increased valence band energy, leading to acceleration of the electron transfer by creating an interaction of nitrogen's free electrons with Cd(II), which subsequently increases the peak current value.

The spatially informed mFISHseq assay resolves biomarker discordance and predicts treatment response in breast cancer.

Current assays fail to address breast cancer's complex biology and accurately predict treatment response. On a retrospective cohort of 1082 female breast tissues, we develop and validate mFISHseq, which integrates multiplexed RNA fluorescent in situ hybridization with RNA-sequencing, guided by laser capture microdissection. This technique ensures tumor purity, unbiased whole transcriptome profiling, and explicitly quantifies intratumoral heterogeneity.

Simvastatin is delivered to the brain by high-strength intranasal cationic SMEDDS and nanoemulsions.

The repurposing of statins as neuroprotective agents and/or anti-brain tumor drugs is limited by challenges in brain bioavailability and systemic off-target effects. Therefore, improved and targeted delivery of statins to the brain is necessary. This study aimed to develop a high-strength liquid formulation of the poorly soluble prodrug simvastatin for intranasal administration, as a strategy to achieve high brain concentrations of the prodrug and/or its active form, tenivastatin.

Metagenomic immunoglobulin sequencing reveals IgA coating of microbial strains in the healthy human gut.

IgA, the primary human antibody secreted from the gut mucosa, shapes the intestinal microbiota. Methodological limitations have hindered defining which microbial strains are targeted by IgA and the implications of binding. Here we develop a technique, metagenomic immunoglobulin sequencing (MIg-seq), that provides strain-level resolution of microbes coated by IgA and use it to determine IgA coating levels for 3,520 gut microbiome strains in healthy human faeces.

Lysozyme-coated nanoparticles for active uptake and delivery of synthetic RNA and plasmid-encoded genes in plants.

Nanoparticle-mediated delivery of nucleic acids and proteins into intact plants has the potential to modify metabolic pathways and confer desirable traits in crops. Here we show that layered double hydroxide (LDH) nanosheets coated with lysozyme are actively taken up into the root tip, root hairs and lateral root junctions by endocytosis, and translocate via an active membrane trafficking pathway in plants. Lysozyme coating enhanced nanosheet uptake by (1) loosening the plant cell wall and (2) stimulating the expression of endocytosis and other membrane trafficking genes.

Correlation of physicochemical properties with antioxidant activity in phenol and thiophenol analogues.

Oxidative stress, associated with excessive production of reactive oxygen and nitrogen species (ROS, RNS), contributes to the development and progression of many ailments, such as aging, cardiovascular diseases, Alzheimer's disease, Parkinson's disease, diabetes, cancer, preeclampsia or multiple sclerosis. While phenols and polyphenols are the most studied antioxidants structurally similar compounds such as anilines or thiophenols are sporadically analyzed despite their radical scavenging potential. This work assesses the impact of structural features of phenols and thiophenols on their antioxidant activity.

Spectroscopic, quantum chemical, and topological calculations of the phenylephrine molecule using density functional theory.

In this work, Density Functional Theory (DFT) on Gaussian 09 W software was utilized to investigate the phenylephrine (PE) molecule (C9H13NO2). Firstly, the optimized structure of the PE molecule was obtained using B3LYP/6-311 + G (d, p) and CAM-B3LYP/6-311 + G (d, p) basis sets. The electron charge density is shown in Mulliken atomic charge as a bar chart and also as a color-filled map in Molecular Electrostatic Potential (MEP).

Importance of reference group selection in the evaluation of cancer incidence.

Elevated cancer incidence has been reported among World Trade Center (WTC)-exposed responders, with some incidence rate ratios (IRRs) varying over time. This study describes the influence that different reference populations have on relative cancer incidence and temporal trends. Participants from the WTC Combined Rescue/Recovery Cohort (n = 65,691) were observed between 1/1/2002 and 12/31/2015 using data obtained from 13 state cancer registries.

The role of pangenomics in orphan crop improvement.

Global food security depends heavily on a few staple crops, while orphan crops, despite being less studied, offer the potential benefits of environmental adaptation and enhanced nutritional traits, especially in a changing climate. Major crops have benefited from genomics-based breeding, initially using single genomes and later pangenomes. Recent advances in DNA sequencing have enabled pangenome construction for several orphan crops, offering a more comprehensive understanding of genetic diversity.