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A pooling–deconvolution algorithm identifies cooperative catalyst behaviours with low experimental cost while accommodating potential inhibitory effects between catalyst candidates.

Cooperation between a chiral hydrogen-bond-donor catalyst and a strong Lewis-acid promoter in an S_N1-type reaction mediates the formation of tertiary carbocations and enables control over enantioselectivity and product distribution.

 The analytical workflow outlined in this study allows multiple crude reaction mixtures to be analysed simultaneously, with substantial reductions in method development and analysis time, and maximizes the chances of finding catalytic systems with broad substrate scope.

A simplified synthesis strategy for stereo- and site-selective glycosylations, using minimally protected mono- and disaccharides and thiourea small-molecule catalysts, enables highly selective functionalization of carbohydrates.

Chiral hydrogen-bond donors bind anions of organometallic catalysts to achieve enantiocontrol and reaction-rate enhancement through ion pairing together with other non-covalent interactions.

Arylpyrrolidino amidothiourea catalysts are shown to catalyse the enantioselective ring-opening of episulfonium ions by indole derivatives. Catalysis and enantioinduction are achieved by selective transition-state stabilization of the major pathway in the rate- and selectivity-determining step through a network of attractive anion-binding, cation–π and hydrogen-bonding interactions between the catalyst and the reacting partners.

The Cancer Genome Atlas Research Network reports an integrative analysis of more than 400 samples of clear cell renal cell carcinoma based on genomic, DNA methylation, RNA and proteomic characterisation; frequent mutations were identified in the PI(3)K/AKT pathway, suggesting this pathway might be a potential therapeutic target, among the findings is also a demonstration of metabolic remodelling which correlates with tumour stage and severity.

A small-molecule (646 Da) hydrogen-bond-donor catalyst accelerates the S_N2 step of an enantioselective Michaelis–Arbuzov reaction by recapitulating the geometric preorganization principle used by enzymes.

Warming temperatures and interactions between plants are the main drivers of changes in Arctic plant communities in response to climate change, and there is no evidence of overall biotic homogenization.

In the Indo-Pacific, multiple Anguilla eel species overlap in their spawning. Here, the authors sequence three Anguilla genomes and with genome-wide data of four more congeners, investigate contemporary hybridization, historical introgression, and the maintenance of species boundaries despite substantial gene flow.

In a phase 1b/2a trial, the combination of the oral PI3K inhibitor duvelisib and romidepsin had limited toxicity and exhibited encouraging clinical activity in patients with relapsed or refractory T cell lymphoma, suggesting an approach whereby PI3K inhibitors can be safely used in this patient population.

Single-cell- and metagenomics-based study reveals two members of the candidate genus ‘Entotheonella’, symbionts of the marine sponge Theonella swinhoei; distinct biosynthetic gene clusters that account for most of the bioactive polyketides and peptides known from T. swinhoei are shown to be attributable to a single member of the T. swinhoei Y microbiome.

Efficient methods for the synthesis of enantioenriched α-amino acids — the building blocks of proteins — have been developed, but it remains a challenge to obtain non-natural amino acids. A new catalytic asymmetric method is now reported for the syntheses of highly enantiomerically enriched non-natural amino acids using a simple and robust chiral amido-thiourea catalyst. The method also uses a safer source of cyanide.

Nucleophilic aromatic substitution reactions have long been thought to occur primarily via stepwise mechanisms. New and sensitive methodology for measuring carbon kinetic isotope effects now shows that most such substitutions actually occur through concerted mechanisms.

Mixed Lineage Kinase Domain-Like (MLKL) pseudokinase is phosphorylated by RIPK3 kinase prior to cell death by necroptosis. Here, the authors use monobodies that bind to the MLKL pseudokinase domain as tools, which allowed them to determine the crystal structures of the MLKL pseudokinase domain in two distinct conformations. By combining their structural data with cell signalling assays and MD simulations they provide evidence that endogenous MLKL preassociates with its upstream regulator RIPK3, and that MLKL disengages from RIPK3 following the induction of necroptosis.

Comprehensive analyses of 178 lung squamous cell carcinomas by The Cancer Genome Atlas project show that the tumour type is characterized by complex genomic alterations, with statistically recurrent mutations in 11 genes, including TP53 in nearly all samples; a potential therapeutic target is identified in most of the samples studied.

The isotopic composition of oceanic basalts suggests that they are composed of true recycled oceanic crust and sediments, which are mixed with the depleted mantle.

Bioactive molecules frequently contain several very similarly reactive functional groups and it can thus be difficult to cause one to react selectively. Now, two separate studies present complementary approaches to this desirable goal.

Producing sufficient food to support the planet’s growing population places enormous strain on critical ecosystems. Quantifying and mapping the individual and cumulative pressures from greenhouse gases, freshwater use, habitat disturbance and nutrient pollution provides crucial insight into producing lower-impact, more sustainable foods.

The Cancer Genome Atlas reports on molecular evaluation of 295 primary gastric adenocarcinomas and proposes a new classification of gastric cancers into 4 subtypes, which should help with clinical assessment and trials of targeted therapies.

Michael Talkowski, David FitzPatrick, Erica Davis and colleagues report rare inherited or de novo missense variants in SMCHD1 in arhinia patients. Some of the same mutations in SMCHD1 are known to cause a phenotypically distinct muscular dystrophy disorder, FSHD2, and the distinct clinical features of the two disorders suggests that additional genes interact with SMCHD1 to cause arhinia.

The Cancer Genome Atlas consortium reports on their genome-wide characterization of somatic alterations in colorectal cancer; in addition to revealing a remarkably consistent pattern of genomic alteration, with 24 genes being significantly mutated, the study identifies new targets for therapeutic intervention and suggests an important role for MYC-directed transcriptional activation and repression.

This paper reports integrative molecular analyses of urothelial bladder carcinoma at the DNA, RNA, and protein levels performed as part of The Cancer Genome Atlas project; recurrent mutations were found in 32 genes, including those involved in cell-cycle regulation, chromatin regulation and kinase signalling pathways; chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far.

An acid has been found to catalyse the formation of a common chemical group, the spiroacetals, and to control which mirror-image isomer of the group is made. The key to success is the acid's bulky molecular structure. See Letter p.315

Carbonyls and alkenes, two of the most common functional groups in organic chemistry, generally do not react with one another. Now, a simple Lewis acid has been shown to catalyse metathesis between alkenes and ketones in a new carbonyl olefination reaction.

An integrative genomic analysis of several hundred endometrial carcinomas shows that a minority of tumour samples carry copy number alterations or TP53 mutations and many contain key cancer-related gene mutations, such as those involved in canonical pathways and chromatin remodelling; a reclassification of endometrial tumours into four distinct types is proposed, which may have an effect on patient treatment regimes.

Michael Talkowski and colleagues analyze balanced chromosomal abnormalities in 273 individuals by whole-genome sequencing. Their findings suggest that sequence-level resolution improves prediction of clinical outcomes for balanced rearrangements and provides insight into pathogenic mechanisms such as altered gene regulation due to changes in chromosome topology.

DICER is involved in the processing of miRNAs, where the RNase IIIa and IIIb domains are thought to cut the 3p and 5p hairpin arms, respectively. Here, in endometrial cancer, the authors identify an RNase IIIa mutation, which phenocopies mutations in the RNase IIIb domain.

Expansion of short tandem repeats can impair RNA and protein function and cause diseases through four main mechanisms: transcription repression, RNA gelation and sequestration of RNA-binding proteins, protein gain of function, and repeat-associated non-AUG toxic translation. Synergy between these mechanisms exacerbates disease, but also offers promising therapeutic targets.

Chronic lymphocytic leukemia is an indolent disease, and many patients succumb to infection rather than the direct effects of the disease. Here, the authors use medical records and machine learning to predict the patients that may be at risk of infection, which may enable a change in the course of their treatment.

T- and NK-cell lymphomas (TCL) are a group of lymphoid malignancies characterized by poor prognosis, but the absence of appropriate pre-clinical models has hampered the development of effective therapies. Here the authors establish several pre-clinical models and identify vulnerabilities that could be further exploited to treat patients afflicted by these diseases.

The Cancer Genome Atlas Network describe their multifaceted analyses of primary breast cancers, shedding light on breast cancer heterogeneity; although only three genes (TP53, PIK3CA and GATA3) are mutated at a frequency greater than 10% across all breast cancers, numerous subtype-associated and novel mutations were identified.

The Cancer Genome Atlas presents an integrative genome-wide analysis of genetic alterations in 279 head and neck squamous cell carcinomas (HNSCCs), which are classified by human papillomavirus (HPV) status; alterations in EGFR, FGFR, PIK3CA and cyclin-dependent kinases are shown to represent candidate targets for therapeutic intervention in most HNSCCs.

Kjerulff et al. evaluate 47 biomarkers, including markers of inflammation and vascular stress, and their associations with demographic and lifestyle factors in healthy participants from the Danish Blood Donor study. Circulating biomarker levels varied according to sex, age, BMI and smoking status.

In a study of children with high genetic risk aged 2 years or older, a risk score integrating pancreatic islet autoantibodies, genetic factors and family history is highly predictive of type 1 diabetes in the subsequent 8 years.

Establishing the relative transmissibility of emerging variants of SARS-CoV-2 is key for pandemic management. Here, the authors use full-population administrative data from Denmark linked to PCR test results and estimate that the Alpha variant was ~60% higher than other strains circulating in early 2021.

Tetrahydroisoquinolines, biologically important organic frameworks, can be prepared in enantio-enriched form via the Poparov reaction using a two-catalyst system consisting of an achiral Brønsted acid and a chiral sulfinamido urea derivative.

Current clinical practice is organized according to tissue or organ of origin of tumors. Now, The Cancer Genome Atlas (TCGA) Research Network has started to identify genomic and other molecular commonalities among a dozen different types of cancer. Emerging similarities and contrasts will form the basis for targeted therapies of the future and for repurposing existing therapies by molecular rather than histological similarities of the diseases.