Tumour-specific proline vulnerability uncovered by differential ribosome codon reading.

Tumour growth and metabolic adaptation may restrict the availability of certain amino acids for protein synthesis. It has recently been shown that certain types of cancer cells depend on glycine, glutamine, leucine and serine metabolism to proliferate and survive. In addition, successful therapies using L-asparaginase-induced asparagine deprivation have been developed for acute lymphoblastic leukaemia. However, a tailored detection system for measuring restrictive amino acids in each tumour is currently not available. Here we harness ribosome profiling for sensing restrictive amino acids, and develop diricore, a procedure for differential ribosome measurements of codon reading. We first demonstrate the functionality and constraints of diricore using metabolic inhibitors and nutrient deprivation assays. Notably, treatment with L-asparaginase elicited both specific diricore signals at asparagine codons and high levels of asparagine synthetase (ASNS). We then applied diricore to kidney cancer and discover signals indicating restrictive proline. As for asparagine, this observation was linked to high levels of PYCR1, a key enzyme in proline production, suggesting a compensatory mechanism allowing tumour expansion. Indeed, PYCR1 is induced by shortage of proline precursors, and its suppression attenuated kidney cancer cell proliferation when proline was limiting. High PYCR1 is frequently observed in invasive breast carcinoma. In an in vivo model system of this tumour, we also uncover signals indicating restrictive proline. We further show that CRISPR-mediated knockout of PYCR1 impedes tumorigenic growth in this system. Thus, diricore has the potential to reveal unknown amino acid deficiencies, vulnerabilities that can be used to target key metabolic pathways for cancer treatment.

Integrating knowledge on biophysical and socioeconomic potential to map clusters for future milk production in Ethiopia.

Despite growing milk demand and imports, market-oriented milk production and formal processing in Ethiopia is limited to areas around Addis Ababa, notwithstanding its competing land use demand. This study assessed biophysical and market potential for developing the dairy sector, characterizing Ethiopian dairy clusters. Biophysical data from geographic information system (GIS) sources and information from key informants were combined in mapping and ranking these clusters on milk production potential. Twenty-four indicators in six major categories were applied for this assessment: feed availability, environmental conditions for dairy cattle, current production status, access to inputs and services, output market access, and production expansion potential. Feed availability (fodder, crop residues, and agro-industrial by-products as well as land availability and affordability) were the main drivers for dairy development, followed by the current production status, mainly driven by number of (improved) dairy cattle and (formal) milk volumes. Dairy clusters close to Addis Ababa had the highest overall scores for development potential, mainly determined by local demand and access to inputs. For dairy sustainable dairy development in Ethiopia, companies seeking long-term opportunities may avoid the Addis Ababa area and develop dairy production and processing in other clusters especially in Amhara and Tigray regions, with good milk production potential but less developed market infrastructure. The combination of biophysical data and key informant knowledge offered key strengths in delivering valuable results within a short time span. It however requires a careful selection of knowledgeable key informants whose expertise cover a broad scope of the dairy value chain.

TGFß1-induced leucine limitation uncovered by differential ribosome codon reading.

Cancer cells modulate their metabolic networks to support cell proliferation and a higher demand of building blocks. These changes may restrict the availability of certain amino acids for protein synthesis, which can be utilized for cancer therapy. However, little is known about the amino acid demand changes occurring during aggressive and invasive stages of cancer. Recently, we developed diricore, an approach based on ribosome profiling that can uncover amino acid limitations. Here, we applied diricore to a cellular model in which epithelial breast cells respond rapidly to TGFß1, a cytokine essential for cancer progression and metastasis, and uncovered shortage of leucine. Further analyses indicated that TGFß1 treatment of human breast epithelial cells reduces the expression of SLC3A2, a subunit of the leucine transporter, which diminishes leucine uptake and inhibits cell proliferation. Thus, we identified a specific amino acid limitation associated with the TGFß1 response, a vulnerability that might be associated with aggressiveness in cancer.

The westernmost tarsier: a new genus and species from the Miocene of Pakistan.

As the closest living sister group of anthropoids, tarsiers (Family Tarsiidae) are an important group in primate evolution. However, their fossil record is poor: only four species have been described, two from the Eocene of China and two from the Miocene of Thailand. All are from outside the range of the living species, which occur only on islands off Southeast Asia. Here, we describe a new fossil tarsier from Pakistan, a significant range extension. This record consists of two lower molars, an upper molar, and a lower premolar found in the Miocene Manchar Formation (~18-16 Ma [millions of years ago]) of Sindh Province, southern Pakistan. The Pakistani tarsier is morphologically distinct from all living and fossil tarsiers, but most similar to the middle Miocene Thai species Tarsius thailandicus. Though living tarsiers have traditionally been classified in a single genus, a recent revision proposed a division into three genera, which is strongly supported by molecular data. The Pakistani species is not referable to any of these genera, and we create for it and T. thailandicus a new tarsiid genus. This discovery broadens our understanding of the geographic range and morphological diversity of Miocene tarsiers and helps to put the living tarsiers into their evolutionary context.

The nomenclature of the blond capuchin, Cebus flavius (Schreber, 1799) (Mammalia, Primates, Cebidae).

I review the nomenclatural history of the blond capuchin, Cebus flavius (Schreber), a Brazilian monkey species. The name was published in 1799, not 1774 as generally cited, so the species is correctly known as Cebus flavius (Schreber, 1799).