Explore the vast range of titles available.

Key Clinical Message We add two novel variants to the existing mutation spectrum of ASNS gene. Loss of ASNS function should be suspected in newborns presenting with congenital microcephaly, intellectual disability, progressive cerebral atrophy, and intractable seizures. Acquisition and sequencing of stored newborn blood spot can be a valuable option when no biological samples are available from a deceased child. We add two novel variants to the existing mutation spectrum of ASNS gene. Loss of ASNS function should be suspected in newborns presenting with congenital microcephaly, intellectual disability, progressive cerebral atrophy, and intractable seizures. Acquisition and sequencing of stored newborn blood spot can be a valuable option when no biological samples are available from a deceased child.

Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be trivially classified into simple (e.g. deletion, translocation) or complex (e.g. chromothripsis, chromoplexy) structural variant classes. Applying a genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,833 tumor whole genome sequences (WGS), we identify three novel complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are \"towers\" of low-JCN duplications associated with early replicating regions and superenhancers, and are enriched in breast and ovarian cancers. Rigma comprise \"chasms\" of low-JCN deletions at late-replicating fragile sites in esophageal and other gastrointestinal (GI) adenocarcinomas. Tyfonas are \"typhoons\" of high-JCN junctions and fold back inversions that are enriched in acral but not cutaneous melanoma and associated with a previously uncharacterized mutational process of non-APOBEC kataegis. Clustering of tumors according to genome graph-derived features identifies subgroups associated with DNA repair defects and poor prognosis. Footnotes * Affiliations, acknowledgements, references, and typographical errors.

Plants are continuously exposed to agents such as herbivores and environmental mechanical stresses that cause wounding and open the way to the invasion by microbial pathogens. Wounding provides nutrients to pathogens and facilitates their entry into the tissue and subsequent infection. Plants have evolved constitutive and induced defense mechanisms to properly respond to wounding and prevent infection. The constitutive defenses are represented by physical barriers, i.e., the presence of cuticle or lignin, or by metabolites that act as toxins or deterrents for herbivores. Plants are also able to sense the injured tissue as an altered self and induce responses similar to those activated by pathogen infection. Endogenous molecules released from wounded tissue may act as Damage-Associated Molecular Patterns (DAMPs) that activate the plant innate immunity. Wound-induced responses are both rapid, such as the oxidative burst and the expression of defense-related genes, and late, such as the callose deposition, the accumulation of proteinase inhibitors and of hydrolytic enzymes (i.e., chitinases and gluganases). Typical examples of DAMPs involved in the response to wounding are the peptide systemin, and the oligogalacturonides, which are oligosaccharides released from the pectic component of the cell wall. Responses to wounding take place both at the site of damage (local response) and systemically (systemic response) and are mediated by hormones such as jasmonic acid, ethylene, salicylic acid, and abscisic acid.

The RAS proteins are GTP-dependent switches that regulate signaling pathways and are frequently mutated in cancer. RAS proteins concentrate in the plasma membrane via lipid-tethers and hypervariable region side-chain interactions in distinct nano-domains. However, little is known about RAS membrane dynamics and the details of RAS activation of downstream signaling. Here, we characterize RAS in live human and mouse cells using single-molecule-tracking methods and estimate RAS mobility parameters. KRAS4b exhibits confined mobility with three diffusive states distinct from the other RAS isoforms (KRAS4a, NRAS, and HRAS); and although most of the amino acid differences between RAS isoforms lie within the hypervariable region, the additional confinement of KRAS4b is largely determined by the protein’s globular domain. To understand the altered mobility of an oncogenic KRAS4b, we used complementary experimental and molecular dynamics simulation approaches to reveal a detailed mechanism.

Conserved microbe-associated molecular patterns (MAMPs) and damage-associated molecular patterns (DAMPs) act as danger signals to activate the plant immune response. These molecules are recognized by surface receptors that are referred to as pattern recognition receptors. Oligogalacturonides (OGs), DAMPs released from the plant cell wall homogalacturonan, have also been proposed to act as local signals in the response to wounding. The Arabidopsis Wall-Associated Kinase 1 (WAK1), a receptor of OGs, has been described to form a complex with a cytoplasmic plasma membrane-localized kinase-associated protein phosphatase (KAPP) and a glycine-rich protein (GRP-3) that we find localized mainly in the cell wall and, in a small part, on the plasma membrane. By using Arabidopsis plants overexpressing WAK1, and both grp-3 and kapp null insertional mutant and overexpressing plants, we demonstrate a positive function of WAK1 and a negative function of GRP-3 and KAPP in the OG-triggered expression of defence genes and the production of an oxidative burst. The three proteins also affect the local response to wounding and the basal resistance against the necrotrophic pathogen Botrytis cinerea. GRP-3 and KAPP are likely to function in the phasing out of the plant immune response.

Environmental impacts of textile production increased over the last decades. This also led to an increasing demand for sustainable textiles and ecolabels, which intend to provide information on environmental aspects of textiles for the consumer. The goal of the paper is to assess selected labels with regard to their strengths and weaknesses, as well as their coverage of relevant environmental aspects over the life cycle of textiles. We applied a characterization scheme to analyse seven selected labels (Blue Angel Textiles, bluesign®, Cotton made in Africa (CMiA), Cradle to Cradle CertifiedTM, Global Organic Textile Standard (GOTS), Global Recycled Standard (GRS), VAUDE Green Shape), and compared their focus to the environmental hotpots identified in the product environmental footprint case study of t-shirts. Most labels focus on the environmental aspects toxicity, water use, and air emissions predominantly in the upstream life cycle phases of textiles (mainly garment production), whereas some relevant impacts and life cycle phases like water in textile use phase remain neglected. We found significant differences between the ecolabels, and none of them cover all relevant aspects and impacts over the life cycle. Consumers need to be aware of these limitations when making purchase decisions.

Introduction: Major depressive disorder (MDD) is more prevalent in women, but men with MDD may experience higher suicide risk and a different symptom profile. This study investigates the subjective impact of MDD on health-related quality of life (HR-QoL) in males and females. Methods: A cross-sectional analysis was conducted on a representative sample from six Italian regions. MDD diagnoses were determined through semi-structured clinical interviews, and HR-QoL was assessed using the SF-12 questionnaire. Mania, hypomania, and subthreshold hypomanic symptoms were evaluated using the Mood Disorder Questionnaire (MDQ). Results: Women had a higher prevalence of MDD (6.2%) than men (3.5%). However, men with MDD showed significantly lower HR-QoL scores compared to non-depressed males, with a greater difference than that observed in women. No significant sex differences emerged in psychiatric comorbidities, but men showed a trend toward higher MDQ positivity, possibly indicating a different depressive phenotype. Conclusions: Although less frequently diagnosed in men, MDD appears to have a stronger perceived impact on quality of life in males. This finding may reflect under-recognized symptoms such as irritability, hyperactivity, and social rhythm dysregulation. Gender-sensitive screening and intervention strategies are essential to improve early detection and reduce the untreated burden of depression in men, ultimately supporting more equitable mental health outcomes.

The use of collagen membranes has remained the gold standard in GTR/GBR. In this study, the features and the biological activities of an acellular porcine dermis collagen matrix membrane applicable during dental surgery were investigated, and also by applying hydration with NaCl. Thus, two tested membranes were distinguished, the H-Membrane and Membrane, compared to the control cell culture plastic. The characterization was performed by SEM and histological analyses. In contrast, the biocompatibility was investigated on HGF and HOB cells at 3, 7, and 14 days by MTT for proliferation study; by SEM and histology for cell interaction study; and by RT-PCR for function-related genes study. In HOBs seeded on membranes, mineralization functions by ALP assay and Alizarin Red staining were also investigated. Results indicated that the tested membranes, especially when hydrated, can promote the proliferation and attachment of cells at each time. Furthermore, membranes significantly increased ALP and mineralization activities in HOBs as well as the osteoblastic-related genes ALP and OCN. Similarly, membranes significantly increased ECM-related and MMP8 gene expression in HGFs. In conclusion, the tested acellular porcine dermis collagen matrix membrane, mainly when it is hydrated, behaved as a suitable microenvironment for oral cells.

Apigenin (APG), a natural flavonoid compound with anti-inflammatory and antioxidative properties, was found to promote in vitro osteogenic differentiation and to accelerate in vivo bone formation, indicating APG as a promising molecule in bone repair, with potential clinical application in bone-deficient conditions. In particular, in dentistry, it is fundamental to increase the available bone volume for implant placement in the maxilla. Therefore, this study aims to investigate the APG effects on osteoblasts (hOBs) obtained from a human jaw. hOBs were incubated with increasing concentrations of APG (5, 10, 20 µM) to assess cell viability and morphology at 24 h and proliferation at 48 and 72 h. Upon establishing the absence of cytotoxicity and any morphological changes, APG showed a stimulating effect on cell growth, with significative results using 5 µM (5-APG) at 48 h. Thus, 5-APG was chosen for further investigations in order to assess alkaline phosphate (ALP) at 7 days, mineralization at 14 days and expression of ALP, Osteocalcin (OCN) and Collagen 1 (COL1) genes at 7 days. Our results showed that 5-APG accelerated osteoblast mineralization activities and significantly upregulated ALP and COL1 gene expression. Hence, this study demonstrated that APG is able to promote human oral osteoblasts proliferation and mineralization, suggesting its potential usefulness in dentistry.

Esophageal adenocarcinoma (EAC) is a highly lethal cancer type with an overall poor survival rate. Twenty to thirty percent of EAC overexpress the human epidermal growth factor receptor 2 (Her2), a transmembrane receptor tyrosine kinase promoting cell growth and proliferation. Patients with Her2 overexpressing breast and gastroesophageal cancer may benefit from Her2 inhibitors. Therapy resistance, however, is well documented. Since autophagy, a lysosome-dependent catabolic process, is implicated in cancer resistance mechanisms, we tested whether autophagy modulation influences Her2 inhibitor sensitivity in EAC. Her2-positive OE19 EAC cells showed an induction in autophagic flux upon treatment with the small molecule Her2 inhibitor Lapatinib. Newly generated Lapatinib-resistant OE19 (OE19 LR) cells showed increased basal autophagic flux compared to parental OE19 (OE19 P) cells. Based on these results, we tested if combining Lapatinib with autophagy inhibitors might be beneficial. OE19 P showed significantly reduced cell viability upon double treatment, while OE19 LR were already sensitive to autophagy inhibition alone. Additionally, Her2 status and autophagy marker expression (LC3B and p62) were investigated in a treatment-naïve EAC patient cohort (n = 112) using immunohistochemistry. Here, no significant correlation between Her2 status and expression of LC3B and p62 was found. Our data show that resistance to Her2-directed therapy is associated with a higher basal autophagy level, which is not per se associated with Her2 status. Therefore, we propose that autophagy may contribute to acquired resistance to Her2-targeted therapy in EAC, and that combining Her2 and autophagy inhibition might be beneficial for EAC patients.