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We conducted a two-sample Mendelian randomization study to test the hypothesis that raised plasma levels of the branched-chain amino acids isoleucine, leucine, and valine are associated with Alzheimer’s disease (AD). From a genome-wide association study of 16,596 individuals of European ancestry, we obtained summary statistics for four independent single nucleotide polymorphisms (SNPs) associated with isoleucine levels and one SNP associated with both leucine and valine levels at genome-wide significance. Summary statistics of the associations of the five SNPs with AD were obtained from the International Genomics of Alzheimer’s Project (17,008 AD cases and 37,154 controls). Based on four SNPs, the odds ratio of AD per genetically predicted one standard deviation higher isoleucine levels was 1.35 (95% CI, 1.08–1.69; p  = 0.007). The leucine- and valine-raising allele was not associated with AD ( p  = 0.46). These data suggest that a genetic predisposition to raised plasma isoleucine levels is positively associated with AD.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year. Whole-exome analysis of individuals with developmental disorders shows that de novo mutations can equally cause loss or altered protein function, but that most mutations causing altered protein function have not yet been described. De novo mutations in developmental disorders Matthew Hurles, Jeremy McRae and colleagues from the Deciphering Developmental Disorders Study report exome sequencing of 4,293 families containing individuals with severe, undiagnosed developmental disorders. They find enrichment of damaging de novo mutations in 94 genes, implicating them in developmental disorders. They estimate that 42% of the cohort carry pathogenic de novo mutations in coding sequences resulting in disrupted or altered protein function.

The authors analyzed the exome sequences of 2,104 intellectual disability patients and their parents. They identified 10 novel candidate genes associated with specific clinical phenotypes. To identify candidate genes for intellectual disability, we performed a meta-analysis on 2,637 de novo mutations, identified from the exomes of 2,104 patient–parent trios. Statistical analyses identified 10 new candidate ID genes: DLG4 , PPM1D , RAC1 , SMAD6 , SON , SOX5 , SYNCRIP , TCF20 , TLK2 and TRIP12 . In addition, we show that these genes are intolerant to nonsynonymous variation and that mutations in these genes are associated with specific clinical ID phenotypes.

Prognostic systems for myelodysplasia rely on clinical factors, but particular genetic lesions can influence relapse rate, overall survival, and nonrelapse-related mortality as well as the choice of conditioning regimen for hematopoietic stem-cell transplantation. The myelodysplastic syndrome (MDS) is clinically and biologically heterogeneous. In children and young adults, MDS can arise in the context of congenital mutations that cause bone marrow failure syndromes or inherited predisposition to myeloid cancers. 1 Therapy-related MDS develops as a late complication in patients with previous exposure to chemotherapy, radiation therapy, or both. 2 In most patients, however, primary MDS arises in the absence of an identified exposure, prodromal bone marrow failure syndrome, or inherited predisposition. Although allogeneic hematopoietic stem-cell transplantation is the only curative therapy for MDS, mortality after transplantation is high, with deaths attributable to relapsed disease and to . . .

Serine/threonine kinases (STKs) and serine/threonine phosphatases (STPs) are widely present across various organisms and play crucial roles in regulating cellular processes such as growth, proliferation, signal transduction, and other physiological functions. Recent research has increasingly focused on the regulation of STKs and STPs in bacteria. STKs have been well studied, identified and characterized in a variety of bacterial species. However, the role of STPs in bacteria remains less understood, and the number of proteins characterized is limited. It has been found that most of the STPs characterized in bacteria were Mg 2+ /Mn 2+ dependent 2C protein phosphatases (PP2Cs), but the evolutionary relationship and taxonomic distribution of bacterial PP2C phosphatases were still not fully elucidated. In this study, we utilized bacterial PP2C phosphatase sequences from the InterPro database to perform a phylogenetic analysis, categorizing the family into five groups. Based on this classification, we examined the evolutionary relationships, species distribution, sequence and structural variations, and domain distribution characteristics of bacterial PP2C phosphatases. Our analysis uncovered evidence of a common evolutionary origin for bacterial PP2C phosphatases. These findings advance the understanding of PP2C phosphatases, offering valuable insights for future functional studies of bacterial serine/threonine phosphatases and aiding in the design of targeted therapeutics for pathogenic bacteria.

PPM1D encodes a serine/threonine phosphatase that regulates numerous pathways including the DNA damage response and p53. Activating mutations and amplification of PPM1D are found across numerous cancer types. GSK2830371 is a potent and selective allosteric inhibitor of PPM1D, but its mechanism of binding and inhibition of catalytic activity are unknown. Here we use computational, biochemical and functional genetic studies to elucidate the molecular basis of GSK2830371 activity. These data confirm that GSK2830371 binds an allosteric site of PPM1D with high affinity. By further incorporating data from hydrogen deuterium exchange mass spectrometry and sedimentation velocity analytical ultracentrifugation, we demonstrate that PPM1D exists in an equilibrium between two conformations that are defined by the movement of the flap domain, which is required for substrate recognition. A hinge region was identified that is critical for switching between the two conformations and was directly implicated in the high-affinity binding of GSK2830371 to PPM1D. We propose that the two conformations represent active and inactive forms of the protein reflected by the position of the flap, and that binding of GSK2830371 shifts the equilibrium to the inactive form. Finally, we found that C-terminal truncating mutations proximal to residue 400 result in destabilization of the protein via loss of a stabilizing N- and C-terminal interaction, consistent with the observation from human genetic data that nearly all PPM1D mutations in cancer are truncating and occur distal to residue 400. Taken together, our findings elucidate the mechanism by which binding of a small molecule to an allosteric site of PPM1D inhibits its activity and provides insights into the biology of PPM1D. In this work, the authors report a sophisticated combination of genetic, biophysical, and biochemical analyses to identifies the cycling conformational states of PPM1D. The findings reveal how an allosteric inhibitor locks the protein into a conformationally inactive state, and explain the distribution of PPM1D activating mutations in cancer.

Clonal expansion in aged normal tissues has been implicated in the development of cancer. However, the chronology and risk dependence of the expansion are poorly understood. Here we intensively sequence 682 micro-scale oesophageal samples and show, in physiologically normal oesophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1 ), which is substantially accelerated by alcohol consumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and increase their number and size with ageing, and ultimately replace almost the entire oesophageal epithelium in the extremely elderly. Compared with mutations in oesophageal cancer, there is a marked overrepresentation of NOTCH1 and PPM1D mutations in physiologically normal oesophageal epithelia; these mutations can be acquired before late adolescence (as early as early infancy) and significantly increase in number with heavy smoking and drinking. The remodelling of the oesophageal epithelium by driver-mutated clones is an inevitable consequence of normal ageing, which—depending on lifestyle risks—may affect cancer development. In physiologically normal epithelia, age-related expansion of clones that carry mutations in NOTCH1 and other driver genes is accelerated by risk factors for developing oesophageal squamous cell carcinoma, such as alcohol consumption or smoking.

Land plants are considered monophyletic, descending from a single successful colonization of land by an aquatic algal ancestor. The ability to survive dehydration to the point of desiccation is a key adaptive trait enabling terrestrialization. In extant land plants, desiccation tolerance depends on the action of the hormone abscisic acid (ABA) that acts through a receptor-signal transduction pathway comprising a PYRABACTIN RESISTANCE 1-like (PYL)–PROTEIN PHOSPHATASE 2C (PP2C)–SNF1-RELATED PROTEIN KINASE 2 (SnRK2) module. Early-diverging aeroterrestrial algae mount a dehydration response that is similar to that of land plants, but that does not depend on ABA: Although ABA synthesis is widespread among algal species, ABA-dependent responses are not detected, and algae lack an ABA-binding PYL homolog. This raises the key question of how ABA signaling arose in the earliest land plants. Here, we systematically characterized ABA receptor-like proteins from major land plant lineages, including a protein found in the algal sister lineage of land plants. We found that the algal PYL-homolog encoded by Zygnema circumcarinatum has basal, ligand-independent activity of PP2C repression, suggesting this to be an ancestral function. Similarly, a liverwort receptor possesses basal activity, but it is further activated by ABA. We propose that co-option of ABA to control a preexisting PP2C-SnRK2-dependent desiccation-tolerance pathway enabled transition from an all-or-nothing survival strategy to a hormone-modulated, competitive strategy by enabling continued growth of anatomically diversifying vascular plants in dehydrative conditions, enabling them to exploit their new environment more efficiently.

Clade A protein phosphatase 2Cs (PP2C-As) play crucial roles in plant stress responses. Although the ABA receptors PYLs inhibit PP2C-As in an ABA-dependent manner, other modulators of these phosphatases remain largely unknown. Here, we identify the FORKED-LIKE 7 (FL7) protein as a broad PP2C-A interactor that effectively suppresses PP2C activity through an ABA-independent, noncompetitive mechanism. By inhibiting PP2C-A activity, FL7 positively regulates osmotic tolerance and plant immunity in an ABA-independent manner. The N-terminal auxin canalisation (AC) domain of FL7 is required for its PP2C-As inhibitory activity. Further evolutionary analyses reveal that FL7 homologues containing an AC domain belong to an ancient family that emerged in a common ancestor of Klebsormidiophyceae algae and land plants. Genetic analyses indicate that algal FL7 homologues have a conserved function as PP2C-A inhibitors. Our study reveals an ABA-independent layer of PP2C-A modulation that regulates biotic and abiotic stress responses, which is likely conserved across a billion years of streptophyte evolution and predated the PYL-ABA regulation established in the common ancestor of land plants. Li et al. reveal an ABA-independent layer of PP2C-A modulation that regulates both biotic and abiotic stress responses. This mechanism is conserved across approximately a billion years and predates the PYL-ABA regulatory system established in the common ancestor of land plants.

The plant hormone indole-3-acetic acid (IAA or auxin) mediates the elongation growth of shoot tissues by promoting cell expansion. According to the acid growth theory proposed in the 1970s, auxin activates plasma membrane H⁺-ATPases (PM H⁺-ATPases) to facilitate cell expansion by both loosening the cell wall through acidification and promoting solute uptake. Mechanistically, however, this process is poorly understood. Recent findings in Arabidopsis (Arabidopsis thaliana) have demonstrated that auxin-induced SMALL AUXIN UP RNA (SAUR) genes promote elongation growth and play a key role in PM H⁺-ATPase activation by inhibiting PP2C.D family protein phosphatases. Here, we extend these findings by demonstrating that SAUR proteins also inhibit tomato PP2C.D family phosphatases and that AtSAUR19 overexpression in tomato (Solanum lycopersicum) confers the same suite of phenotypes as previously reported for Arabidopsis. Furthermore, we employ a custom image-based method for measuring hypocotyl segment elongation with high resolution and a method for measuring cell wall mechanical properties, to add mechanistic details to the emerging description of auxin-mediated cell expansion. We find that constitutive expression of GFP-AtSAUR19 bypasses the normal requirement of auxin for elongation growth by increasing the mechanical extensibility of excised hypocotyl segments. In contrast, hypocotyl segments overexpressing a PP2C.D phosphatase are specifically impaired in auxin-mediated elongation. The time courses of auxin-induced SAUR expression and auxindependent elongation growth were closely correlated. These findings indicate that induction of SAUR expression is sufficient to elicit auxin-mediated expansion growth by activating PM H⁺-ATPases to facilitate apoplast acidification and mechanical wall loosening.