Novel invasive genotypes can arise through polyploidisation, hybridisation, or gene flow between populations of distinct origins or related species. Solidago gigantea, a notorious European invader, has long been reported exclusively as tetraploid in its invasive range. Recently, mixed-ploidy populations, including tetraploid and pentaploid plants, were discovered; yet the potential role of the novel pentaploid cytotype (and its progeny) in S. gigantea invasions remains poorly understood. This study aims to elucidate the origin of pentaploids and the cytotype and genetic structure of mixed-ploidy populations, characterise the reproductive mode and mating interactions of pentaploid plants, and assess their fitness and potential contribution to invasiveness using relative DNA content screening, ddRADseq population genetics, and reproductive potential and fitness assessments. Molecular analyses revealed that pentaploids constitute a genetically distinct lineage within S. gigantea. Our results rule out both an autopolyploid origin from the common tetraploid cytotype and an allopolyploid origin via hybridisation with co-occurring native or invasive Solidago species. The pentaploid cytotype reproduces exclusively through clonal propagation; its low genetic variability suggests that the two studied populations may belong to a single extensive clonal genet. Pentaploids produce viable gametes but appear to exhibit strict self-incompatibility, preventing the formation of offspring within the same genotype. However, pentaploid S. gigantea engages in bidirectional mating with co-occurring tetraploid plants, yielding well-developed seeds with offspring ploidy ranging from 4x to 5x (predominantly aneuploid). Despite this cytological variability, progeny from mixed-ploidy populations displayed germination rates and early growth comparable to those from pure tetraploid populations. Notably, at least some tetraploid offspring from 4x-5x crosses successfully established, flowered, and backcrossed with pentaploid plants to produce viable seeds of subsequent introgressed generations. The pentaploid cytotype of S. gigantea introduces a new post-invasion dynamic to its invasive populations. Rather than being an evolutionary dead-end, this cytotype may potentially enhance the species' invasiveness through three evolutionary pathways: (1) a highly successful clonal life strategy enabling both local and long-distance spread; (2) genetic enrichment of tetraploid populations via ongoing interploidy crosses; and (3) establishment of novel aneuploid genotypes due to the remarkable tolerance of chromosomal instability observed in S. gigantea.
Anaerobic gut bacteria have highly evolved functions that promote transmission between human hosts. These include resilient spores produced by many Bacillota (formerly Firmicutes) bacteria, which are tolerant to extended ambient oxygen exposure. Recent culturing and genomic studies have revealed the taxonomic diversity of gut spore-formers and their prevalence in human populations. However, due to a reliance on spore-forming model organisms that are not representative of commensal gut bacteria, we still have a limited understanding of gut microbiome-specific sporulation processes and their underlying genetics. In this opinion article, we outline a rational path for development of new model organisms derived from commensal spore-forming gut bacteria in order to obtain fundamental insights into sporulation and to provide a discovery platform for novel probiotic or microbiome-based therapeutic development.
How host organisms adapt their defense systems to newly invading transposable elements remains poorly understood. Here, we show how Drosophila melanogaster acquired PIWI-interacting RNA (piRNA)-mediated immunity against the endogenous retrovirus Tirant. We uncover two distinct modes of de novo piRNA biogenesis by combining genetics, small RNA profiling, and population genomics. The primary route involves antisense insertions into the flamenco cluster, a master locus for transposon control. Unexpectedly, a second, equally potent mechanism arises from antisense Tirant insertions within host gene 3' UTRs. This process requires host gene transcription but is independent of host gene identity. Our findings challenge prevailing models that tie piRNA precursor specification to genomic origin or nuclear RNA processing context. Instead, they reveal a flexible mechanism that turns a critical vulnerability of transposons into an advantage for the host. When transposition occurs into host gene exons, chimeric antisense transcripts are exported to the cytoplasm, inadvertently initiating piRNA production and enabling rapid, adaptive genome defense against new invaders.
With coral reefs increasingly threatened by rapid environmental changes, understanding genetic diversity at microgeographic scale is critical for assessing their capacity to respond to local stress regimes. Theory for continuous populations predicts that brooding corals with restricted dispersal should exhibit fine-scale genetic structure and isolation-by-distance, yet such patterns remain poorly resolved in marginal and environmentally extreme reef ecosystems. Here, we investigated the genetic structure of the catch bowl coral, Isopora cf. palifera, across 11 sites within ~ 14 km in Kenting National Park (KNP), southern Taiwan, a reefscape characterized by strong small-scale environmental heterogeneity, including chronic thermal influence from a nuclear power plant and tidally driven upwelling. We genotyped 466 colonies (six microsatellite loci yielding 302 unique multilocus genotypes) and sequenced nuclear PaxC 46/47-intron from 322 colonies of I. cf. palifera. Microsatellite data revealed strong genetic structure (K = 2, K = 5): principal coordinate analyses identified four geographic groupings, and Bayesian clustering (STRUCTURE) supported two major clusters separating Nanwan (plus Tantzei Bay) from the remaining coastal sites, with one site (Shiaowan) showing admixture. The PaxC marker resolved ten haplotypes, with H1 widespread, H2 concentrated along Nanwan, and H3 dominant at thermally influenced sites near the nuclear power plant outfall. Overall, populations showed high site differentiation, significant isolation-by-distance, and high self-recruitment (68-92%), indicating limited effective dispersal. A temporal comparison (2000-2015) at Tantzei Bay indicated stable genetic structure through time despite repeated regional disturbances. Generalized estimating equation (GEE) models showed that site-level seawater temperature was positively associated with both host haplotype composition (GEE; coefficient = 0.0479, p < 0.001) and Symbiodiniaceae genera (GEE; coefficient = 0.0462, p < 0.001, symbiont data from a previous work in KNP), suggesting non-random host-symbiont-environment associations at microgeographic scale. Together, these results indicate that I. cf. palifera in KNP exhibits pronounced fine-scale genetic structure consistent with restricted dispersal and possible microgeographic adaptation of the holobiont to local thermal regimes. While such structuring may enhance local resilience by maintaining diverse, site-specific host-symbiont combinations, it also implies limited scope for rescue via gene flow if future warming pushes populations beyond their adapted tolerances. Our findings underscore the importance of accounting for microgeographic genetic structure and local adaptation when designing management and conservation strategies for reefscape such as those in KNP.
Covalent Bruton tyrosine kinase (BTK) inhibitors have advanced the treatment of Waldenström macroglobulinaemia; however, the occurrence of progression, intolerance, and acquired resistance are not fully understood. We aim to report on the safety and activity of pirtobrutinib (a highly selective, non-covalent BTK inhibitor) in patients with relapsed or refractory Waldenström macroglobulinaemia, including those who received previous covalent BTK inhibitors as part of the phase 1/2 BRUIN trial. The BRUIN study was an open-label, multicentre, phase 1/2 trial that enrolled patients with relapsed or refractory B-cell malignancies from 29 sites across eight countries. Patients aged 18 years or older who previously received BTK inhibitor-containing regimens, had an Eastern Cooperative Oncology Group performance status of 0-2, and histologically confirmed Waldenström macroglobulinaemia were eligible. In phase 1, patients received 100-300 mg oral pirtobrutinib once a day in 28-day cycles and the recommended phase 2 dose (RP2D) of 200 mg pirtobrutinib once a day was determined. The phase 2 primary endpoint was antitumour activity of pirtobrutinib based on objective response rate as assessed by an investigator in patients with chronic lymphocytic leukaemia, small lymphocytic leukaemia, or mantle cell lymphoma. In patients with Waldenström macroglobulinaemia, response was evaluated using the Sixth International Workshop on Waldenström Macroglobulinemia (IWWM-6) criteria. BRUIN is registered with ClinicalTrials.gov, NCT03740529 (completed). BRUIN recruited patients from Aug 12, 2019, to March 14, 2022, and 778 patients received pirtobrutinib. 80 patients had relapsed or refractory Waldenström macroglobulinaemia (n=18 in phase 1 and n=62 in phase 2), with a median age of 68·5 years (IQR 61·0-75·0). 52 (65%) patients were male and 28 (35%) were female. The median number of previous lines of systemic therapy was 3·0 (2·0-5·0). 63 (79%) patients received previous covalent BTK inhibitors. 73 (91%) received 200 mg pirtobrutinib once per day (the RP2D). Using IWWM-6 criteria, the objective response rate was 82·5% (95% CI 72·4-90·1), with one (1·3%) patient reaching complete response, eight (10·0%) reaching very good partial response, 49 (61·3%) reaching partial response, and eight (10·0%) reaching minor response. The median study follow-up was 35·0 months (17·7-47·7). The objective response rate was 81·0% (69·1-89·8) for those who received previous covalent BTK inhibitors and 88·2% (63·6-98·5) for covalent BTK inhibitor-naive patients. Grade 3 or higher treatment-emergent adverse events occurred in 57 (71%) patients, with the most common being neutropenia or neutrophil count decreased (15 [19%]) and anaemia (19 [24%]). Treatment-emergent deaths were reported in five (6%) patients (bacterial sepsis, intracranial haemorrhage, COVID-19 pneumonia, hypertensive cardiomegaly and pneumonia [n=1 each unrelated to treatment], and treatment-related necrotising pneumonia [n=1]). Treatment-emergent adverse events leading to dose reductions occurred in four (5%) patients and pirtobrutinib discontinuation in 12 (15%). Pirtobrutinib was highly active and well tolerated, regardless of previous exposure to covalent BTK inhibitors, and might be a promising new therapeutic option for patients with relapsed or refractory Waldenström macroglobulinaemia, particularly in those previously exposed to covalent BTK inhibitors, for whom durable and effective treatments are needed. Eli Lilly and Company.
Apricot (Prunus armeniaca L.), a globally cultivated temperate fruit crop, represents an economically critical species for fresh consumption and value-added products. Despite its agricultural importance, genomic resources have lagged behind other Prunus species, hampering trait dissection and molecular breeding. Here, we present the first telomere-to-telomere (T2T) gap-free genome assembly for the elite cultivar 'Sungold', achieved through the integration of multi-platform sequencing technologies: Illumina short-read, PacBio HiFi, ONT ultra-long, and Hi-C scaffolding. The final assembly spans 251.36 Mb with benchmark quality metrics: a contig N50 of 32.04 Mb, BUSCO completeness score of 98.8%, LTR Assembly Index (LAI) of 15.99, and a consensus quality value (QV) of 59.75. The T2T assembly achieved the resolution of all eight centromeres, together with fourteen intact telomeres, confirming its high structural integrity. Genomic annotation revealed 43.38% of repetitive sequences and 25,999 predicted protein-coding genes. This gap-free T2T genome resource establishes the highest-resolution reference for investigating apricot genome evolution, structural variation, and trait-associated genetic mechanisms in modern breeding programs.
Itch is a complex noxious sensation associated with many skin and systemic conditions, which varies in intensity and quality across different body regions. Despite its prevalence, the molecular and cellular mechanisms underlying regional itch differences remain poorly understood. Investigating the neural basis of regional itch differences, we identified a functional divergence in neuropeptide signaling and central circuit engagement between the trigeminal and spinal systems, which was independent of peripheral innervation density. Utilizing a combination of behavioral, pharmacological, genetic, and molecular assays, we identified a unique population of trigeminal (TG) neurons that facilitate specialized itch-pain coding. Our results indicate that while histamine receptors HRH1 and HRH3 are both involved in mediating mixed itch-and-pain sensations, the specific activity of Substance P (SP)- and Somatostatin (SST)-expressing neurons orchestrates this transition in the cheek. This behavioral shift is mediated by a central mechanism wherein sensory neurons activation recruits distinct nociceptive circuits within the brainstem. In brief, these findings provide insights into the molecular and cellular mechanisms underlying regional itch differences, highlighting the importance of considering anatomical location when developing targeted treatments.
Variants in the ATP6V0A1 gene, which encodes the α1 subunit of the V0 domain of the V-ATPases, are associated with developmental and epileptic encephalopathy 104 (DEE104). This study aimed to characterize the clinical features of a Chinese patient with ATP6V0A1 variants and facilitate the early diagnosis and treatment. We report a case of a 13-month-old Chinese girl with DEE who presented with developmental delay, acute onset of clustered focal seizures, and status epilepticus. Physical examination revealed hypotonia and microcephaly. Brain MRI showed mildly enlarged bilateral lateral ventricles, a thin corpus callosum, and progressive cerebral atrophy. Genetic analysis identified a de novo missense mutation in the ATP6V0A1 gene (c.2222G > A, p.R741Q). While her epilepsy was refractory to multiple antiepileptic drugs, her seizures were controlled effectively with oxcarbazepine (OXC). We identified a patient with DEE104 carrying a de novo ATP6V0A1 mutation, whose clinical presentation included developmental delay, clustered focal seizures, and status epilepticus. Our findings provide further support for considering OXC in the management of ATP6V0A1-related epilepsy.
Therapeutic resistance to chemotherapy or radiotherapy is a significant issue in several cancers, including head and neck squamous cell carcinoma (HNSCC). One pathway associated with therapeutic resistance is the NFκB pathway, which promotes survival in response to the cytokine TNFα, a key mediator of chemotherapy and radiotherapy-induced cytotoxicity. However, direct targeting of the NFκB pathway is associated with significant toxicity and thus targeting the regulation of this pathway is a promising therapeutic target. We recently demonstrated that the USP14/UCHL5 inhibitor b-AP15 inhibits NFκB activity, inhibiting proliferation and inducing apoptosis in HNSCC cells. Furthermore, b-AP15 treatment sensitised HNSCC cells to the cytotoxic effects of TNFα, as well as TNF-inducing radiation treatment. Here, we investigated if b-AP15 sensitised HNSCC cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a cancer selective member of the TNF family. b-AP15 treatment sensitised HNSCC cells to TRAIL treatment. Mechanistically, we show that b-AP15 induced expression of the TRAIL receptor Death Receptor 5 (DR5)/TRAIL Receptor 2 (TRAILR2), which was required for b-AP15-mediated TRAIL sensitisation. b-AP15 induced reactive oxygen species (ROS) and activated the JNK signalling pathway and both ROS and JNK signalling were required for the induction of DR5 expression and TRAIL sensitisation. We further show that b-AP15-mediated reduction of the NFκB-dependent gene XIAP induced DR5 expression and TRAIL sensitisation and that combination between b-AP15 and IAP antagonists was synergistic in HNSCC cells in vitro. Our data further define the mechanism of b-AP15-mediated cytotoxicity and highlight potential combination treatments that warrant further exploration in pre-clinical studies in HNSCC.
Climate-driven heat stress disrupts metabolic homeostasis in livestock, yet the molecular mechanisms underlying adaptive responses remain poorly understood. Here, we integrated newly generated plasma metabolomic data from 111 heat-stressed cows with previously published whole-genome sequencing datasets from the same animals, identifying 30 metabolic markers and 27 copy number variations (CNVs) associated with 25 candidate genes involved in the regulation of these metabolites. Notably, a CNV hotspot encompassing CIITA emerged as a key pleiotropic locus strongly associated with acylcarnitine levels, body weight, and rectal temperature. Heat exposure suppressed CIITA expression in skeletal muscle, correlating with impaired myogenic development. We demonstrate that CIITA overexpression in vitro induces coordinated remodeling of cell cycle-related gene expression and partially alleviates heat-induced inhibition of myoblast proliferation. Moreover, CIITA overexpression markedly suppresses long-chain fatty acid β-oxidation and mitochondrial electron transport activity, accompanied by reduced adenosine triphosphate production, suggesting that CIITA may limit metabolic heat generation by constraining mitochondrial metabolic flux. Overall, these findings position CIITA as a central integrative regulator linking immune function, energy metabolism, and cell proliferation during bovine adaptation to heat stress, and highlight a potential genetic target for improving thermotolerance in livestock.
To interpret and transmit biological signals, proteins use correlated motions. Experimental determination of these dynamics and the structural distributions they generate remains a key challenge. Here, using 1146 crystal structures of the main protease (Mpro) from SARS-CoV-2, we were able to infer a model of the enzyme's structural fluctuations. Mpro is regulated by concentration, becoming enzymatically active after forming a homodimer. To understand the structural changes that enable dimerization to activate catalysis, we employed our model, predicting which regions of the dimerization domain are structurally correlated with the active site. Mutations at these positions, expected to disrupt catalysis, resulted in a dramatic reduction in activity in one case, a mild effect in the second, and none in the third. Additional crystallography and biophysical experiments provide a mechanistic explanation for these results. Our work suggests that a statistical crystallography, in which numerous crystallographic datasets are analyzed, can reveal the structural fluctuations of protein native states and help uncover their biological function.
Mesomelic dysplasia Savarirayan-type or ID4-related (MDST) is an ultra-rare skeletal dysplasia caused by chromosome 6p22.3 microdeletions. To date, only four cases have been reported. Here, we report a fifth case, a 9 year-old female with severe mesomelic lower limb shortening and characteristic radiographic findings, highly resembling those identified in previous MDST patients. No deletion was identified by array. However, whole genome sequencing (WGS) revealed a de novo inversion at 6p22.3. As hypothesized for deletions detected in this disorder we predict that the structural variant disrupts several topologically associated domains (TADs) in the region and is likely to place ID4 in closer proximity to more telomerically located limb enhancers, which could result in enhancer adoption and potentially lead to ID4 limb misexpression. Thus, this case broadens the genetic spectrum in MDST and provides further support to the role of ID4 dysregulation as the main underlying molecular mechanism of this ultra-rare skeletal disorder.
Parents of undiagnosed children (POUC) experience significant psychosocial challenges, including anxiety, uncertainty, and isolation, that stem from parenting medically complex children while facing obstacles throughout the diagnostic journey. Despite these well-described challenges, a mental health intervention designed to meet the unique needs of POUC, which is necessary to promote the psychological and overall wellbeing of this population, does not exist. Acceptance and Commitment Therapy (ACT) has proven effective in a wide range of populations and shows promise for POUC. With the goal of designing and implementing an ACT-based intervention tailored to POUC, this pre-implementation study aimed to understand their psychosocial needs and prior mental health support experiences, explore their reactions towards ACT, and determine their anticipated barriers, facilitators, and preferences for participating in an ACT skills group, guided by the Consolidated Framework for Implementation Research (CFIR). Semi-structured, individual interviews were conducted with 18 POUC, including an experiential portion that exposed participants to key ACT concepts and exercises. Inductive coding based on participant responses and deductive coding based on the CFIR were employed to code interview transcripts. Reflexive thematic analysis was performed to identify key findings. Isolation was a psychosocial challenge for which all participants desired support. Many participants reported inadequacies in their prior mental health support, primarily due to lack of understanding from therapy providers regarding their unique circumstances. Although most participants indicated that ACT could help them manage difficult thoughts and emotions and act in alignment with their values, they also described achievability, collaboration, and accountability as key elements that could support their uptake. The main barriers, facilitators, and preferences that participants highlighted were related to group design (accessibility, flexibility) as well as their own characteristics as recipients (capability, need, and motivation). This pre-implementation study affirmed the potential value of ACT for POUC and identified key opportunities for tailoring an ACT skills group to meet their needs. Future research, including pilot implementation studies, are needed to evaluate the effectiveness of a tailored ACT skills group and further refine both the intervention and its implementation strategy.
Representatives of the phylum Methanobacteriota occur in various anoxic environments, but only members of the genera Methanosphaera and Methanobrevibacter exclusively colonize the digestive tract of animals. Recent phylogenomic analyses revealed that the genus Methanobrevibacter, which harbors the majority of the intestinal species, is severely underclassified and represents a family-level taxon, "Methanobrevibacteraceae", that evolved entirely in the digestive tract of animals. Comparative genome analysis of 158 species of Methanobacteriota, including uncultured representatives in the Genome Taxonomy Database (GTDB), demonstrated that the intestinal lineages are clearly separated from the remaining members of the phylum. They differ from the non-intestinal lineages in genome size, GC content, coding density, an increased number of pseudogenes and adhesin-like proteins, and show numerous adaptations to the copiotrophic gut environment. A decreased biosynthetic potential led to a dependence on other community members and limits the dispersal of intestinal species into other habitats, which is reflected in coevolutionary patterns with their major host groups among arthropods, ungulates, and primates. Certain lineages even engaged in symbiotic associations with intestinal protists, presumably benefiting from the H2 produced by the hydrogenosomes of their anaerobic hosts. Our results reveal that the transition of free-living Methanobacteriota to a host-associated lifestyle involves the same genomic changes that were previously recognized in gut bacteria and bacterial endosymbionts of protists, reflecting resemblances between the two prokaryotic domains that are caused by evolutionary convergence in similar environments.
Placental histopathology provides important insights into maternal and fetal health, yet the organ's spatial heterogeneity poses significant challenges for objective and reproducible histological analysis. Systematic assessment of cellular and structural composition across placental slides remains limited by the scale and subjectivity of manual evaluation. Quantitative approaches are therefore needed to characterise placental responses to injury beyond visually apparent lesions. We applied the Histology Analysis Pipeline.PY (HAPPY), a biologically inspired hierarchical deep learning framework for quantitative single-cell-resolution analysis of Haematoxylin and Eosin (H&E) slides, to 130 placental parenchyma slides from 62 singleton full-term live births. The dataset included healthy normal controls and four common placental lesion types: infarction, perivillous fibrin, avascular villi, and intervillous thrombosis. Cell-type and tissue-structure compositions were quantified, and slide-level deviation from a healthy reference was assessed using compositional data analysis. Placental slides with lesions exhibited significant cellular composition differences compared with healthy controls, including increased extravillous trophoblast and leukocyte densities and decreased Hofbauer cell densities. These cellular changes were accompanied by tissue-level alterations, particularly increased fibrin deposition and changes in villous structure. Compositional deviation increased with infarction size but not with other lesion types. Notably, compositional differences were also detected in slides without an apparent lesion from placentas with lesion(s) elsewhere, indicating organ-wide responses extending beyond focal pathology. Quantitative deep phenotyping reveals widespread cellular and structural changes associated with placental lesions, including effects not evident on routine histological assessment. These findings demonstrate the potential of AI-based digital histology to complement conventional placental pathology in research and clinical settings.
Marine microalgae are frequently promoted as sustainable biofuel feedstocks because of their halotolerance, high photosynthetic efficiency, and limited land requirements, yet commercial deployment remains elusive. This gap is primarily systemic rather than biological, reflecting the fragmented development of strain engineering, harvesting, conversion, and sustainability assessment. This review reframes marine microalgae as circular biofactories and advances a system-centric paradigm for integrated biorefineries. We synthesise recent advances in metabolic and genetic engineering, low-energy harvesting, and thermochemical and biochemical conversion, highlighting how cross-stage interdependencies dominate overall performance. We further discuss how artificial intelligence, digital twins, nutrient recycling, carbon utilisation, and high-value coproducts enable predictive optimisation and techno-economic viability. This perspective provides a road map for translating marine microalgal biofuels from laboratory promise to industrial relevance.
Cornelia de Lange syndrome is a rare congenital disorder marked by considerable clinical variability, including intellectual disability, growth retardation, distinctive facial features, limb abnormalities, and multisystem involvement. The condition is primarily linked to mutations in genes encoding components of the cohesin complex that are essential for chromosomal stability and gene regulation. We report a case of a mild type of Cornelia de Lange syndrome caused by a de novo mutation in an Iranian family. We investigated a 19-year-old Iranian male individual presenting with developmental delay, borderline intellectual disability, dysmorphic facial features, and multisystem involvement. Whole-exome sequencing was performed to identify causative variants. A de novo heterozygous variant affecting the start codon of NIPBL (NM_133433.4:c.2T>A; NP_597677.2:p.Met1Lys) was identified. This variant was absent from population databases and predicted to disrupt normal translation initiation. Sanger sequencing and co-segregation analysis confirmed the genetic findings. In silico tools and population databases were utilized to assess variant pathogenicity. Clinically, the patient exhibited classical Cornelia de Lange syndrome features with relatively mild intellectual impairment compared with typical loss-of-function cases, consistent with the hypothesis of potential use of alternative start sites. This case shows a known NIPBL start-loss variant's correlation with a relatively mild clinical presentation and offers more genotype-phenotype evidence for it. This finding suggests a possible role for downstream translation initiation as a modifier of disease severity, although further functional validation is required. Comprehensive genetic analysis remains essential for accurate diagnosis, prognosis, and counseling in patients with Cornelia de Lange syndrome.
The plastic pollution crisis urges innovative recycling solutions. Promising approaches especially for polyester-containing wastes include enzymatic hydrolysis and microbial upcycling. For efficient enzymatic hydrolysis of polyesters, elevated temperatures (70-80 °C) are required, necessitating thermophilic microbial chassis for consolidated bioprocessing (CBP). In this study, we engineered Geobacillus thermoleovorans through adaptive laboratory evolution (ALE) for robust growth on adipic acid (AA) and 1,4-butanediol (BDO), two relevant monomers for example derived from poly(butylene adipate-co-terephthalate) (PBAT), enabling growth rates of up to 0.10 h-1 on AA and 0.13 h-1 on BDO. Based on a high-quality annotated genome sequence of the wild type, genomic mutations and gene expression levels were characterized in mutants grown on the respective substrates compared to glucose. For BDO, an alcohol dehydrogenase (Gth_001044) and an aldehyde dehydrogenase (Gth_001082) were identified to be likely responsible for its oxidative degradation. AA uptake appears to be mediated by a dicarboxylate transporter (Gth_003270), followed by CoA activation and β-oxidation involving a CoA transferase (Gth_003192) and several upregulated CoA-family dehydrogenases. To demonstrate applicability of these strains in plastic upcycling, they were co-cultivated with PBAT as the sole carbon source in combination with the cutinase HiC for PBAT hydrolysis. This resulted in growth on the released AA and BDO. Given the potential to purify the remaining terephthalate (TA), this approach highlights the feasibility of selective monomer valorization in bioprocesses. Additional ALE enabled co-utilization of AA and BDO by a single strain and improved AA consumption at lower concentrations, underscoring the strains' adaptability and high potential for plastic upcycling applications. KEY POINTS: • G. thermoleovorans evolved for robust growth on adipate and 1,4-butanediol at 60 °C. • Genome and transcriptome analyses revealed underlying pathways and enzymes involved. • Co-cultivation of the evolved strains on PBAT with HiC as the sole carbon source.
These guidelines replace the previous (2019) UK guidelines for the medical and laboratory screening of sperm, egg and embryo donors and were achieved by a joint working group composed of representatives from the Association of Reproductive and Clinical Scientists (ARCS), the British Fertility Society (BFS), the British Association for Sexual Health and HIV (BASHH) and the British HIV Association (BHIVA), with review and comments from their respective memberships. It was written to guide best practice in clinics but is not intended as a tool to judge the practice of centres within the UK or beyond. Guidance on core information that should be supplied to all parties involved in donation is provided. Screening tests and standards required are summarized, as are specific considerations for known donation and embryo donation. The assessment of genetic risk and heritable disorders has been fundamentally reviewed in light of technological advances. Extended carrier screening is also discussed, although we do not suggest that this is routinely performed.
Lysosomes and peroxisomes are essential for cellular homeostasis, yet how their activities are coordinated remains poorly understood. Here, we identify peroxisome-derived ether lipids as key regulators of lysosomal function. A genome-wide CRISPR/Cas9 screen in LYSET-deficient mucolipidosis V cells revealed that disruption of ether lipid synthesis genes or peroxins markedly reduces lysosome accumulation and restores degradative capacity. Genetic or pharmacological inhibition of ether lipid synthesis enhanced lysosomal exocytosis and promoted the clearance of undigested material independently of mannose-6-phosphate trafficking. Conversely, supplementation with the ether lipid precursor hexadecylglycerol increased lysosome abundance, while reducing their degradative capacity. These findings uncover a peroxisome-lysosome metabolic axis, in which ether lipids act as bidirectional regulators of lysosomal number and function independently of the lysosomal master regulator TFEB. Our findings reveal how peroxisome-localized lipid metabolism modulates lysosomal homeostasis, and suggest potential new strategies to combat lysosomal and peroxisomal disorders.