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Marco Tartaglia and colleagues report the identification of mutations of SHOC2 in individuals with Noonan-like syndrome with loose anagen hair. The mutations cause aberrantly acquired N-myristoylation of SHOC2 resulting in aberrant targeting of SHOC2 to the plasma membrane. SHOC2 is believed to function as a scaffold linking RAS to downstream signal transducers. N-myristoylation is a common form of co-translational protein fatty acylation resulting from the attachment of myristate to a required N-terminal glycine residue 1 , 2 . We show that aberrantly acquired N-myristoylation of SHOC2, a leucine-rich repeat–containing protein that positively modulates RAS-MAPK signal flow 3 , 4 , 5 , 6 , underlies a clinically distinctive condition of the neuro-cardio-facial-cutaneous disorders family. Twenty-five subjects with a relatively consistent phenotype previously termed Noonan-like syndrome with loose anagen hair (MIM607721) 7 shared the 4A>G missense change in SHOC2 (producing an S2G amino acid substitution) that introduces an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. Expression of SHOC2 S2G in vitro enhanced MAPK activation in a cell type–specific fashion. Induction of SHOC2 S2G in Caenorhabditis elegans engendered protruding vulva, a neomorphic phenotype previously associated with aberrant signaling. These results document the first example of an acquired N-terminal lipid modification of a protein causing human disease.

Chemosensory receptors play a crucial role in distinguishing the wide range of volatile/soluble molecules by binding them with high accuracy. Chemosensation is the main sensory modality in organisms lacking long-range sensory mechanisms like vision/hearing. Despite its low number of sensory neurons, the nematode Caenorhabditis elegans possesses several chemosensory receptors, allowing it to detect about as many odorants as mammals. Here, we show that C. elegans displays attraction towards urine samples of women with breast cancer, avoiding control ones. Behavioral assays on animals lacking AWC sensory neurons demonstrate the relevance of these neurons in sensing cancer odorants: calcium imaging on AWC increases the accuracy of the discrimination (97.22%). Also, chemotaxis assays on animals lacking GPCRs expressed in AWC allow to identify receptors involved in binding cancer metabolites, suggesting that an alteration of a few metabolites is sufficient for the cancer discriminating behavior of C. elegans , which may help identify a fundamental fingerprint of breast cancer.

The identification of genes that confer either extension of life span or accelerate age-related decline was a step forward in understanding the mechanisms of aging and revealed that it is partially controlled by genetics and transcriptional programs. Here, we discovered that the human DNA sequence C16ORF70 encodes a protein, named MYTHO (macroautophagy and youth optimizer), which controls life span and health span. MYTHO protein is conserved from Caenorhabditis elegans to humans and its mRNA was upregulated in aged mice and elderly people. Deletion of the orthologous myt-1 gene in C . elegans dramatically shortened life span and decreased animal survival upon exposure to oxidative stress. Mechanistically, MYTHO is required for autophagy likely because it acts as a scaffold that binds WIPI2 and BCAS3 to recruit and assemble the conjugation system at the phagophore, the nascent autophagosome. We conclude that MYTHO is a transcriptionally regulated initiator of autophagy that is central in promoting stress resistance and healthy aging.

Background Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are neurodevelopmental conditions caused by genetic variants leading to upregulated signaling in the RAS-MAPK pathway. While previous research has focused on genetic variability in cognitive and cardiac phenotypes, behavioral phenotypes, and their correlations across genetic variants and within the PTPN11 gene remain poorly characterized. Methods This study included 121 individuals with NS ( PTPN11 : 88, SOS1 : 18, RAF1 : 6, KRAS : 2, RIT1 : 3, NRAS : 2, LZTR1 : 2, SOS2 : 1) and seven individuals with NSML ( PTPN11 ), compared to age- and sex-matched typically developing (TD) (N = 71). Behavioral questionnaires assessed social responsiveness and ASD-related traits (using SRS-2), and emotional problems (using CBCL) to identify genetic variant-specific behavioral profiles. Biochemical profiling of SHP2 activity in PTPN11 -associated NS variants examined genotype–phenotype relationships. Results Compared to TD individuals, those with PTPN11 -associated NS, NSML, and SOS1 -associated NS exhibited clinically elevated scores, indicating increased ASD-related behaviors, poorer social functioning, and heightened emotional problems. Genetic variant comparisons revealed that individuals with PTPN11 -associated NS and NSML exhibited greater ASD-related challenges than those with RAF1 . Individuals with NSML exhibit elevated attention problems compared to all other genetic groups. Logistic regression results suggested each one-unit increase in SHP2 fold activation for PTPN11 -associated NS corresponded to a 64% higher likelihood of markedly elevated restricted and repetitive behaviors, suggesting genotype–phenotype links. Limitations Small sample sizes for rarer variants, leading to unequal group sizes across subgroups, with PTPN11 variants comprising most of the NS group. Future research should address these sampling constraints and conduct functional studies to clarify variant impacts. Longitudinal assessments could elucidate behavioral phenotype trajectories. Conclusions This study underscores the importance of genetic variant-specific research to understand unique behavioral phenotypes in NS and NSML. Our findings indicate a higher risk for ASD-related symptoms in PTPN11 -associated NS and NSML compared to other variants. Additionally, individuals with PTPN11 -associated NS and higher SHP2 fold activation exhibited greater impairments in restricted and repetitive behaviors, suggesting SHP2 activation variations may contribute to phenotypic variability. By linking ASD-related symptoms to biochemical predictors in PTPN11 -associated NS, this study may inform future targeted treatment approaches.

This is an issue edsumm for ng1939. Identification of the Palaeocene/Eocene thermal maximum in a marine sedimentary sequence. It shows that sea surface temperatures near the North Pole increased from roughly 18 degrees Celsius to over 23 degrees Celsius — such warm values imply the absence of ice and thus exclude the influence of ice-albedo feedbacks on this Arctic warming. Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies 1 . Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome 2 , 3 , 4 , 5 , 6 . Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1 , which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome–associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.

Background We previously associated HIST1H1E mutations causing Rahman syndrome with a specific genome-wide methylation pattern. Results Methylome analysis from peripheral blood samples of six affected subjects led us to identify a specific hypomethylated profile. This “episignature” was enriched for genes involved in neuronal system development and function. A computational classifier yielded full sensitivity and specificity in detecting subjects with Rahman syndrome. Applying this model to a cohort of undiagnosed probands allowed us to reach diagnosis in one subject. Conclusions We demonstrate an epigenetic signature in subjects with Rahman syndrome that can be used to reach molecular diagnosis.

The widespread presence of micro- and nanoplastics (MNPs) in the environment represents an emerging risk for human and environment health. New Approach Methodologies (NAMs) offer valuable tools to improve the mechanistic understanding of nanoscale processes and support hazard identification without animal testing. This study investigated the biological effects of exposure to 0–100 µg/mL 100 and 20 nm polystyrene (PS-NPs) and 100 nm polycaprolactone nanoplastics (PCL-NPs) using advanced in vitro intestinal models and the 3R-compliant in vivo Caenorhabditis elegans model. In vitro endpoints included cytotoxicity, oxidative stress, DNA damage, cellular internalization, and barrier integrity, while in vivo analyses focused on oxidative stress and locomotor behavior across multiple exposed generations. PS-NPs induced significant DNA damage in vitro, particularly at ≥50 µg/mL after 24–48 h exposure, and were rapidly internalized by cells, with 20 nm particles also detected in the nucleus. In contrast, 100 nm PCL-NPs elicited weaker biological responses. In vivo, PS-NPs caused an increase in oxidative stress response and locomotor behavior across exposed generations, whereas PCL-NPs produced milder effects, consistent with in vitro findings. These results support the potential of integrated NAMs for assessing human health risks associated with MNP exposure within a One Health framework.

De novo CLTC mutations underlie a spectrum of early-onset neurodevelopmental phenotypes having developmental delay/intellectual disability (ID), epilepsy, and movement disorders (MD) as major clinical features. CLTC encodes the widely expressed heavy polypeptide of clathrin, a major component of the coated vesicles mediating endocytosis, intracellular trafficking, and synaptic vesicle recycling. The underlying pathogenic mechanism is largely unknown. Here, we assessed the functional impact of the recurrent c.2669C > T (p.P890L) substitution, which is associated with a relatively mild ID/MD phenotype. Primary fibroblasts endogenously expressing the mutated protein show reduced transferrin uptake compared to fibroblast lines obtained from three unrelated healthy donors, suggesting defective clathrin-mediated endocytosis. In vitro studies also reveal a block in cell cycle transition from G0/G1 to the S phase in patient’s cells compared to control cells. To demonstrate the causative role of the p.P890L substitution, the pathogenic missense change was introduced at the orthologous position of the Caenorhabditis elegans gene, chc-1 (p.P892L), via CRISPR/Cas9. The resulting homozygous gene-edited strain displays resistance to aldicarb and hypersensitivity to PTZ, indicating defective release of acetylcholine and GABA by ventral cord motor neurons. Consistently, mutant animals show synaptic vesicle depletion at the sublateral nerve cords, and slightly defective dopamine signaling, highlighting a generalized deficit in synaptic transmission. This defective release of neurotransmitters is associated with their secondary accumulation at the presynaptic membrane. Automated analysis of C. elegans locomotion indicates that chc-1 mutants move slower than their isogenic controls and display defective synaptic plasticity. Phenotypic profiling of chc-1 (+/P892L) heterozygous animals and transgenic overexpression experiments document a mild dominant-negative behavior for the mutant allele. Finally, a more severe phenotype resembling that of chc-1 null mutants is observed in animals harboring the c.3146 T > C substitution (p.L1049P), homologs of the pathogenic c.3140 T > C (p.L1047P) change associated with a severe epileptic phenotype. Overall, our findings provide novel insights into disease mechanisms and genotype–phenotype correlations of CLTC -related disorders.

A protein-based film (PBF), obtained from black soldier fly prepupae proteins, was assessed for its agronomic performance as mulch. PBF was investigated in a potting experiment and compared with Mater-Bi (MB), polyethylene (PE) and bare soil. During the experiment, degraded surface area, weight and thickness of the film, water evaporated from the pot, and the soil microbiological content (SMC) were recorded. In addition, films were buried to assess their biodegradability and impact on SMC. During the mulching process, the PBF showed a significant degradation. In terms of evaporated water, the PBF performed similarly to MB and worse than PE. Regarding SMC, film of any nature caused an increase in the Clostridia spp. and a decrease of total mesophilic aerobic bacteria and fungi contents. When buried, only PBF recorded a faster biodegradability, showing a reduction of surface area, thickness and weight. PBF and MB highlighted a significant increase in contents of Clostridia spp., mesophilic aerobic bacteria and fungi. Our results reported, for the first time, the valorization of black soldier fly (BSF) prepupae proteins as a biodegradable film for mulching purposes. However, further study is needed to reduce the PBF biodegradability and allow it to be used for the most important mulched crops.

Background/Objectives: Pathogenic variants in GNAO1, encoding the inhibitory G protein subunit Gαo, cause severe neurodevelopmental disorders that remain largely refractory to pharmacological treatments. Gαo transduces inhibitory signals downstream of multiple G protein-coupled receptors (GPCRs) involved in motor control. Here, we used gene-edited Caenorhabditis elegans models carrying goa-1 variants, the ortholog of GNAO1, to investigate GPCR contributions to Gαo-dependent locomotor phenotypes. Methods: We combined pharmacological screening of dopamine- and cannabinoid-targeting ligands in goa-1 mutants with structural analysis of ligand-binding pocket conservation and genetic perturbation of receptor function using RNAi and knockout approaches. Results: Pharmacological modulation of GPCR signaling produced non-linear and context-dependent effects. Compounds predicted to further increase excitability may instead promote phenotypic improvement, consistent with compensatory network rebalancing. Structural analyses revealed substantial divergence in ligand-binding pocket conservation for several GPCR-ligand pairs, suggesting that altered binding affinity and selectivity may also contribute to the observed phenotypic outcome. Pharmacological experiments performed in GPCR-depleted mutants allowed for the correlation of structural findings with functional effects for selected receptor-ligand pairs. Finally, genetic reduction in GPCRs coupled to stimulatory G proteins ameliorated hyperactive locomotion in goa-1 mutants, whereas reduction in GPCRs coupled to inhibitory G proteins is largely insufficient to induce or exacerbate locomotor defects. Conclusions: Our findings identify excessive excitatory GPCR input as a key modulator of motor dysfunction in the context of impaired Gαo signaling. They also show that structural conservation is a necessary but not sufficient condition to predict functional responses. Overall, this study establishes C. elegans as a suitable platform to dissect GPCR-mediated signaling and highlights the value of integrating pharmacological and genetic approaches to guide target selection in GNAO1-related disorders.