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Chemical methods of achieving asymmetric protonation are classified according to reaction mechanism, with a view to developing a greater understanding of this most fundamental of asymmetric processes, and thus improving the potential for its application in synthesis. Enantioselective protonation is a common process in biosynthetic sequences. The decarboxylase and esterase enzymes that effect this valuable transformation are able to control both the steric environment around the proton acceptor (typically an enolate) and the proton donor (typically a thiol). Recently, several chemical methods for achieving enantioselective protonation have been developed by exploiting various means of enantiocontrol in different mechanisms. These laboratory transformations have proved useful for the preparation of a number of valuable organic compounds. Here, we review recent reports of enantioselective protonations, classifying them according to mechanism, and discuss how a deeper understanding of the processes can lead to improved methods for effecting this most fundamental method of obtaining enantiopure compounds.

Biologically active and structurally complex natural products provide a powerful driving force for the development of novel reaction methodology. Major advances can reshape the way chemists approach the construction of challenging chemical bonds. In this work, we begin by describing the development of a catalytic asymmetric synthesis of five and seven-membered rings containing all-carbon quaternary stereocenters. Enantioselective Pd-catalyzed decarboxylative allylic alkylation reactions of β-ketoester substrates afforded a variety of chiral seven-membered α-quaternary vinylogous esters. Initial attempts to convert these compounds to γ-quaternary cycloheptenones led to the discovery of a two-carbon ring contraction reaction, which provided isomeric γ-quaternary acylcyclopentenes. Subsequent adjustment of reaction parameters provided divergent access to the originally targeted cycloheptenones. Numerous synthetic applications of the two versatile product types are demonstrated. The methodology expands on our previous investigations of six-membered ring scaffolds and provides additional chiral building blocks for asymmetric total synthesis. The ring contraction approach to acylcyclopentenes was further developed in the total synthesis of the presilphiperfolanols, which are important intermediates in sesquiterpene biosynthesis. Key to our synthetic route to the tricyclic core was the application of intramolecular Diels-Alder and Ni-catalyzed 1,4-hydroboration reactions. From these efforts, the enantioselective total synthesis of presilphiperfolan-1β-ol was achieved. Future research efforts seek to extend the synthetic route to presilphiperfolan-9α-ol and study the synthetic compounds in biomimetic carbocation rearrangement processes.

Large Language Models (LLMs), representing a significant achievement in artificial intelligence (AI) research, have demonstrated their ability in a multitude of tasks. This project aims to explore the capabilities of GPT-3.5, a leading example of LLMs, in processing the sentiment analysis of Internet memes. Memes, which include both verbal and visual aspects, act as a powerful yet complex tool for expressing ideas and sentiments, demanding an understanding of societal norms and cultural contexts. Notably, the detection and moderation of hateful memes pose a significant challenge due to their implicit offensive nature. This project investigates GPT's proficiency in such subjective tasks, revealing its strengths and potential limitations. The tasks include the classification of meme sentiment, determination of humor type, and detection of implicit hate in memes. The performance evaluation, using datasets from SemEval-2020 Task 8 and Facebook hateful memes, offers a comparative understanding of GPT responses against human annotations. Despite GPT's remarkable progress, our findings underscore the challenges faced by these models in handling subjective tasks, which are rooted in their inherent limitations including contextual understanding, interpretation of implicit meanings, and data biases. This research contributes to the broader discourse on the applicability of AI in handling complex, context-dependent tasks, and offers valuable insights for future advancements.

35% of patients with pancreatic cancer have unresectable locally advanced disease at diagnosis. Several studies have examined systemic chemotherapy with FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) in patients with locally advanced pancreatic cancer. We aimed to assess the effectiveness of FOLFIRINOX as first-line treatment in this patient population. We systematically searched Embase, MEDLINE (OvidSP), Web of Science, Scopus, PubMed Publisher, Cochrane, and Google Scholar from July 1, 1994, to July 2, 2015, for studies of treatment-naive patients of any age who received FOLFIRINOX as first-line treatment of locally advanced pancreatic cancer. Our primary outcome was overall survival. Secondary outcomes were progression-free survival; rates of grade 3 or 4 adverse events; and the proportion of patients who underwent radiotherapy or chemoradiotherapy, surgical resection after FOLFIRINOX, and R0 resection. We evaluated survival outcomes with the Kaplan–Meier method with patient-level data. Grade 3 or 4 adverse events, and the proportion of patients who underwent subsequent radiotherapy or chemoradiotherapy or resection, were pooled in a random-effects model. We included 13 studies comprising 689 patients, of whom 355 (52%) patients had locally advanced pancreatic cancer. 11 studies, comprising 315 patients with locally advanced disease, reported survival outcomes and were eligible for patient-level meta-analysis. Median overall survival from the start of FOLFIRINOX ranged from 10·0 months (95% CI 4·0–16·0) to 32·7 months (23·1–42·3) across studies with a pooled patient-level median overall survival of 24·2 months (95% CI 21·7–26·8). Median progression-free survival ranged from 3·0 months (95% CI not calculable) to 20·4 months (6·5–34·3) across studies with a patient-level median progression-free survival of 15·0 months (95% 13·8–16·2). In ten studies comprising 490 patients, 296 grade 3 or 4 adverse events were reported (60·4 events per 100 patients). No deaths were attributed to FOLFIRINOX toxicity. The proportion of patients who underwent radiotherapy or chemoradiotherapy ranged from 31% to 100% across studies. In eight studies, 154 (57%) of 271 patients received radiotherapy or chemoradiotherapy after FOLFIRINOX. The pooled proportion of patients who received any radiotherapy treatment was 63·5% (95% CI 43·3–81·6, I2 90%). The proportion of patients who underwent surgical resection for locally advanced pancreatic cancer ranged from 0% to 43%. The proportion of patients who had R0 resection of those who underwent resection ranged from 50% to 100% across studies. In 12 studies, 91 (28%) of 325 patients underwent resection after FOLFIRINOX. The pooled proportion of patients who had resection was 25·9% (95% CI 20·2–31·9, I2 24%). R0 resection was reported in 60 (74%) of 81 patients. The pooled proportion of patients who had R0 resection was 78·4% (95% CI 60·2–92·2, I2 64%). Patients with locally advanced pancreatic cancer treated with FOLFIRINOX had a median overall survival of 24·2 months—longer than that reported with gemcitabine (6–13 months). Future research should assess these promising results in a randomised controlled trial, and should establish which patients might benefit from radiotherapy or chemoradiotherapy or resection after FOLFIRINOX. None.

The ecological and oceanographic processes that drive the response of pelagic ocean microbiomes to environmental changes remain poorly understood, particularly in coastal upwelling ecosystems. Here we show that seasonal and interannual variability in coastal upwelling predicts pelagic ocean microbiome diversity and community structure in the Southern California Current region. Ribosomal RNA gene sequencing, targeting prokaryotic and eukaryotic microbes, from samples collected seasonally during 2014-2020 indicate that nitracline depth is the most robust predictor of spatial microbial community structure and biodiversity in this region. Striking ecological changes occurred due to the transition from a warm anomaly during 2014-2016, characterized by intense stratification, to cooler conditions in 2017-2018, representative of more typical upwelling conditions, with photosynthetic eukaryotes, especially diatoms, changing most strongly. The regional slope of nitracline depth exerts strong control on the relative proportion of highly diverse offshore communities and low biodiversity, but highly productive nearshore communities. Coastal upwelling sustains some of the most productive ocean regions. Here, the authors find that spatial patterns and temporal changes in nutrient supply explain marine microbial community structure and diversity in the Southern California Current region.

Ischaemic diseases such as critical limb ischaemia and myocardial infarction affect millions of people worldwide 1 . Transplanting endothelial cells (ECs) is a promising therapy in vascular medicine, but engrafting ECs typically necessitates co-transplanting perivascular supporting cells such as mesenchymal stromal cells (MSCs), which makes clinical implementation complicated 2 , 3 . The mechanisms that enable MSCs to facilitate EC engraftment remain elusive. Here we show that, under cellular stress, MSCs transfer mitochondria to ECs through tunnelling nanotubes, and that blocking this transfer impairs EC engraftment. We devised a strategy to artificially transplant mitochondria, transiently enhancing EC bioenergetics and enabling them to form functional vessels in ischaemic tissues without the support of MSCs. Notably, exogenous mitochondria did not integrate into the endogenous EC mitochondrial pool, but triggered mitophagy after internalization. Transplanted mitochondria co-localized with autophagosomes, and ablation of the PINK1–Parkin pathway negated the enhanced engraftment ability of ECs. Our findings reveal a mechanism that underlies the effects of mitochondrial transfer between mesenchymal and endothelial cells, and offer potential for a new approach for vascular cell therapy. Under stressful conditions, mesenchymal stromal cells transfer mitochondria to endothelial cells through tunnelling nanotubes, and artificially transplanting mitochondria into endothelial cells improves the ability of these cells to engraft and to revascularize ischaemic tissues.

A near-complete diploid nuclear genome and accompanying circular mitochondrial and chloroplast genomes have been assembled from the elite commercial diatom species Nitzschia inconspicua . The 50 Mbp haploid size of the nuclear genome is nearly double that of model diatom Phaeodactylum tricornutum , but 30% smaller than closer relative Fragilariopsis cylindrus . Diploid assembly, which was facilitated by low levels of allelic heterozygosity (2.7%), included 14 candidate chromosome pairs composed of long, syntenic contigs, covering 93% of the total assembly. Telomeric ends were capped with an unusual 12-mer, G-rich, degenerate repeat sequence. Predicted proteins were highly enriched in strain-specific marker domains associated with cell-surface adhesion, biofilm formation, and raphe system gliding motility. Expanded species-specific families of carbonic anhydrases suggest potential enhancement of carbon concentration efficiency, and duplicated glycolysis and fatty acid synthesis pathways across cytosolic and organellar compartments may enhance peak metabolic output, contributing to competitive success over other organisms in mixed cultures. The N. inconspicua genome delivers a robust new reference for future functional and transcriptomic studies to illuminate the physiology of benthic pennate diatoms and harness their unique adaptations to support commercial algae biomass and bioproduct production.

Nonsense mutations are the underlying cause of approximately 11% of all inherited genetic diseases 1 . Nonsense mutations convert a sense codon that is decoded by tRNA into a premature termination codon (PTC), resulting in an abrupt termination of translation. One strategy to suppress nonsense mutations is to use natural tRNAs with altered anticodons to base-pair to the newly emerged PTC and promote translation 2 – 7 . However, tRNA-based gene therapy has not yielded an optimal combination of clinical efficacy and safety and there is presently no treatment for individuals with nonsense mutations. Here we introduce a strategy based on altering native tRNAs into  efficient suppressor tRNAs (sup-tRNAs) by individually fine-tuning their sequence to the physico-chemical properties of the amino acid that they carry. Intravenous and intratracheal lipid nanoparticle (LNP) administration of sup-tRNA in mice restored the production of functional proteins with nonsense mutations. LNP–sup-tRNA formulations caused no discernible readthrough at endogenous native stop codons, as determined by ribosome profiling. At clinically important PTCs in the cystic fibrosis transmembrane conductance regulator gene ( CFTR ), the sup-tRNAs re-established expression and function in cell systems and patient-derived nasal epithelia and restored airway volume homeostasis. These results provide a framework for the development of tRNA-based therapies with a high molecular safety profile and high efficacy in targeted PTC suppression. Suppressor tRNAs adapted to the amino acid that they carry enable readthrough of premature termination codons introduced by nonsense mutations and show potential for the treatment of genetic diseases such as cystic fibrosis.