AI delivers Michaelis constants as fuel for genome-scale metabolic models

Michaelis constants (Km) are essential to predict the catalytic rate of enzymes, but are not widely available. A new study in PLOS Biology uses artificial intelligence (AI) to accurately predict Km on a proteome-wide scale, paving the way for dynamic, genome-wide modeling of metabolism

Computational repurposing of oncology drugs through off‐target drug binding interactions from pharmacological databases

PurposeSystematic repurposing of approved medicines for another indication may accelerate drug development in oncology. We present a strategy combining biomarker testing with drug repurposing to identify new treatments for patients with advanced cancer.MethodsTumours were sequenced with the Illumina TruSight Oncology 500 (TSO-500) platform or the FoundationOne CDx panel. Mutations were screened by two medical oncologists and pathogenic mutations were categorised referencing literature. Variants of unknown significance were classified as potentially pathogenic using plausible mechanisms and computational prediction of pathogenicity. Gain of function (GOF) mutations were evaluated through repurposing databases Probe Miner (PM), Broad Institute Drug Repurposing Hub (Broad Institute DRH) and TOPOGRAPH. GOF mutations were repurposing events if identified in PM, not indexed in TOPOGRAPH and excluding mutations with a known Food and Drug Administration (FDA)-approved biomarker. The computational repurposing approach was validated by evaluating its ability to identify FDA-approved biomarkers. The total repurposable genome was identified by evaluating all possible gene-FDA drug-approved combinations in the PM dataset.ResultsThe computational repurposing approach was accurate at identifying FDA therapies with known biomarkers (94%). Using next-generation sequencing molecular reports (n = 94), a meaningful percentage of patients (14%) could have an off-label therapeutic identified. The frequency of theoretical drug repurposing events in The Cancer Genome Atlas pan-cancer dataset was 73% of the samples in the cohort.ConclusionA computational drug repurposing approach may assist in identifying novel repurposing events in cancer patients with no access to standard therapies. Further validation is needed to confirm a precision oncology approach using drug repurposing. Repurposing identified Food and Drug Administration-approved drug-biomarker combinations with high sensitivity and specificity. In a real-world dataset, repurposing identified novel drug-biomarker combinations in patients who were ineligible for standard therapies or biomarker-matched trials. Preliminary functional validation was demonstrated for two drug-biomarker combinations. Using The Cancer Genome Atlas data, the potential scope of repurposing was identified. imag

Истражување На Локалитетот Плоча-Миќов Град Кај Градиште (Охридско Езеро) Во 2019 Година

Research In 2019 At The Site Of Ploča-Mićov Grad Near Gradište (Lake Ohrid) [in Mazedonisch]: Локалитетот Плоча-Миќов Град кај Градиште на Охридското Езеро претставу-ва една од најдобро истражените наколни на-селби во балканскиот регион, што овозможува потемелен увид во нејзиниот карактер, но и во заедниците што ја основале и користеле. Покрај придонесот на претходните истражувања на овој локалитет, голем удел во тоа има теков-ниот меѓународен проект EXPLO (Exploring the dynamics and causes of prehistoric land use change in the cradle of European farming), поддржан од Европскиот истражувачки совет. Овој проект е во соработка меѓу Универзитетот во Берн, Уни-верзитетот во Оксфорд и Универзитетот во Со-лун, додека македонски партнери се Центарот за истражување на предисторијата и Заводот за заштита на спомениците на културата и музеј - Охрид во домен на ископувањето на локалите-тот Плоча-Миќов Град. Како резултат на оваа соработка, годинашното истражување вклучи повеќе мултидисциплинарни сфери, како што се дендрохронологијата, археоботаниката, пале-оекологијата, проучувањето на материјалната култура итн. Во таа смисла, истражувањето во 2019 година беше надоврзување на она од прет-ходната година, но во рамки на нов проект и со вклучување на многу поголем тим од стручњаци и студенти, коишто се ангажираа во разни сег-менти од работата на Плоча-Миќов Град

Conserved Roles of CrRLK1L Receptor-Like Kinases in Cell Expansion and Reproduction from Algae to Angiosperms

Receptor-like kinases (RLKs) are regulators of plant development through allowing cells to sense their extracellular environment. They facilitate detection of local endogenous signals, in addition to external biotic and abiotic stimuli. The Catharanthus roseus RLK1-like (CrRLK1L) protein kinase subfamily, which contains FERONIA, plays a central role in regulating fertilization and in cell expansion mechanisms such as cell elongation and tip growth, as well as having indirect links to plant–pathogen interactions. Several components of CrRLK1L signaling pathways have been identified, including an extracellular ligand, coreceptors, and downstream signaling elements. The presence and abundance of the CrRLK1L proteins in the plant kingdom suggest an origin within the Streptophyta lineage, with a notable increase in prevalence in the seeded land plants. Given the function of the sole CrRLK1L protein in a charophycean alga, the possibility of a conserved role in detection and/or regulation of cell wall integrity throughout the Strephtophytes is discussed. Orthologs of signaling pathway components are also present in extant representatives of non-vascular land plants and early vascular land plants including the liverwort Marchantia polymorpha, the moss Physcomitrella patens and the lycophyte Selaginella moellendorffii. Deciphering the roles in development of the CrRLK1L protein kinases in early diverging land plants will provide insights into their ancestral function, furthering our understanding of this diversified subfamily of receptors in higher plants

Haplodiploidy and the reproductive ecology of Arthropods

Approximately 15% of all arthropods reproduce through haplodiploidy. Yet it is unclear how this mode of reproduction affects other aspects of reproductive ecology. In this review we outline predictions on how haplodiploidy might affect mating system evolution, the evolution of traits under sexual or sexual antagonistic selection, sex allocation decisions and the evolution of parental care. We also give an overview of the phylogenetic distribution of haplodiploidy. Finally, we discuss how comparisons between different types of haplodiploidy (arrhenotoky, PGE with haploid vs somatically diploid males) might help to discriminate between the effects of virgin birth, haploid gene expression and those of haploid gene transmission

Target 2035-update on the quest for a probe for every protein

Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function. Accordingly, a subset of human proteins has been at the heart of research interests of scientists over the centuries, and we have accumulated varying degrees of knowledge about approximately 65% of the human proteome. Nevertheless, a large proportion of proteins in the human proteome (∼35%) remains uncharacterized, and less than 5% of the human proteome has been successfully targeted for drug discovery. This highlights the profound disconnect between our abilities to obtain genetic information and subsequent development of effective medicines. Target 2035 is an international federation of biomedical scientists from the public and private sectors, which aims to address this gap by developing and applying new technologies to create by year 2035 chemogenomic libraries, chemical probes, and/or biological probes for the entire human proteome

EXD2 governs germ stem cell homeostasis and lifespan by promoting mitoribosome integrity and translation

Mitochondria are subcellular organelles critical for meeting the bioenergetic and biosynthetic needs of the cell. Mitochondrial function relies on genes and RNA species encoded both in the nucleus and mitochondria, as well as their coordinated translation, import and respiratory complex assembly. Here we describe the characterization of exonuclease domain like 2 (EXD2), a nuclear encoded gene that we show is targeted to the mitochondria and prevents the aberrant association of mRNAs with the mitochondrial ribosome. The loss of EXD2 resulted in defective mitochondrial translation, impaired respiration, reduced ATP production, increased reactive oxygen species and widespread metabolic abnormalities. Depletion of EXD2/CG6744 in D.melanogaster caused developmental delays and premature female germline stem cell attrition, reduced fecundity and a dramatic extension of lifespan that could be reversed with an anti-oxidant diet. Our results define a conserved role for EXD2 in mitochondrial translation that influences development and aging

Obstetric outcomes of sars-cov-2 infection in asymptomatic pregnant women

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER)Around two percent of asymptomatic women in labor test positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Spain. Families and care providers face childbirth with uncertainty. We determined if SARS-CoV-2 infection at delivery among asymptomatic mothers had different obstetric outcomes compared to negative patients. This was a multicenter prospective study based on universal antenatal screening for SARS-CoV-2 infection. A total of 42 hospitals tested women admitted for delivery using polymerase chain reaction, from March to May 2020. We included positive mothers and a sample of negative mothers asymptomatic throughout the antenatal period, with 6-week postpartum follow-up. Association between SARS-CoV-2 and obstetric outcomes was evaluated by multivariate logistic regression analyses. In total, 174 asymptomatic SARS-CoV-2 positive pregnancies were compared with 430 asymptomatic negative pregnancies. No differences were observed between both groups in key maternal and neonatal outcomes at delivery and follow-up, with the exception of prelabor rupture of membranes at term (adjusted odds ratio 1.88, 95% confidence interval 1.13-3.11; p = 0.015). Asymptomatic SARS-CoV-2 positive mothers have higher odds of prelabor rupture of membranes at term, without an increase in perinatal complications, compared to negative mothers. Pregnant women testing positive for SARS-CoV-2 at admission for delivery should be reassured by their healthcare workers in the absence of symptoms

Mitochondrial and cell cycle functions of SLIMP

[eng] The mitochondrial Seryl-tRNA Synthetase (SerRS2) is a member of the class II tRNA synthetase family. The mature enzyme catalyses the ligation of serine to tRNASer in mitochondria. During the process of constructing a model for human disorders caused by mitochondrial tRNA aminoacylation deficiencies in Drosophila melanogaster, a previously uncharacterized paralogue of SerRS2 named Seryl-tRNA synthetase-Like Insect Mitochondrial Protein (SLIMP) was identified. SLIMP is a new type of aminoacyl tRNA synthetase-like protein that has acquired an essential function in insects. This fast evolving paralogue is a mitochondrial RNA-binding protein which lacks tRNA aminoacylation activity. It has been previously demonstrated that mitochondrial SLIMP interacts with its homologue SerRS2 and also with LON protease. We confirmed these interactions and we described the function of SLIMP by depleting its protein levels in Drosophila melanogaster S2 cells, which led to severe defects in mitochondrial function and cell cycle arrest. We found that SLIMP simultaneously acts as a regulator of DNA replication and translation in the mitochondria and, as regulator of cell cycle progression. We show that SLIMP activates mitochondrial protein synthesis through its interaction with SerRS2 and regulates mitochondrial DNA levels by stimulating TFAM digestion by the protease LON. SLIMP was previously reported to be required for correct cell cycle progression. We showed that the depletion of a non-mitochondrial pool of SLIMP causes cell cycle arrest in G2 and the activation of E2F-related and G2/M check-point genes. Our results indicate that SLIMP activity provides an important protein for the communication between mitochondrial anabolism and cell cycle regulation.[cat] La Seril-ARNt Sintetasa mitocondrial (SerRS2) és membre de la família de ARNt sintetases de classe II. Aquest enzim es responsable de la lligació de l’aminoàcid serina al corresponent ARNtSer a la mitocòndria. En el procés de desenvolupament d’un model de malalties mitocondrials causades per deficiències en l’aminoacilació de ARNt en Drosophila melanogaster, es descobrí una proteïna paràleg de SerRS2 no caracteritzada fins el moment, anomenada Seril-ARNt sintetasa-Like Insect Mitochondrial Protein (SLIMP). SLIMP representa una nova classe de proteïna semblant a les ARNt sintetases que ha adquirit funcions essencials en insectes. Aquest paràleg ha evolucionat en poc temps i constitueix una proteïna amb unió a ARN però sense capacitat d’aminoacilació. Prèviament s’havia caracteritzat que SLIMP interacciona amb el seu homòleg SerRS2 i també amb la proteasa mitocondrial LON. Ara hem confirmat aquestes interaccions i hem descrit les funcions de SLIMP, caracteritzant l’efecte de la depleció dels seus nivells proteics en cèl·lules S2 de Drosophila melanogaster, que comportà severs defectes mitocondrials i un arrest del cicle cel·lular. Hem definit que SLIMP actua simultàniament com un regulador de la replicació del ADN i la traducció a la mitocòndria i, com a regulador de la progressió del cicle cel·lular. SLIMP activa la síntesis proteica mitocondrial gràcies a la interacció amb SerRS2, i a més regula els nivells de ADN mitocondrial, estimulant la degradació de TFAM per la proteasa LON. Anteriorment, es descrigué que SLIMP és necessari per la correcta progressió del cicle cel·lular. Hem trobat que la depleció d’una isoforma no mitocondrial de SLIMP arresta el cicle cel·lular en la fase G2 i activa la transcripció de gens relacionats amb E2F i amb el punt de control de G2/M. Aquests resultats indiquen la important tasca de SLIMP per la comunicació entre l’anabolisme mitocondrial i la regulació del cicle cel·lular