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Oculopharyngeal muscular dystrophy is caused by trinucleotide repeat expansions in thePABPN1gene. Here the authors use AAV-based gene therapy to knockdown the mutant gene and replace it with a wild-type allele, and show effectiveness in mice and in patient cells.

Abstract The bigmouth buffalo Ictiobus cyprinellus (Catostomidae) is a freshwater fish native to North America that is known for its longevity. During the 1970s, the bigmouth buffalo was recorded as declining in Canada, Minnesota, and North Dakota and became a protected species in Canada. In the USA, population declines are exacerbated by wasteful recreational bowfishing, lack of fisheries management, and overall lack of knowledge. However, recent studies have revealed the exceptional lifespan of bigmouth buffalo, their negligible senescence, slow growth, delayed maturity, and episodic recruitment. Yet little is known about the spawning phenology of bigmouth buffalo, nor their age demographics in east central Minnesota. In this 2021–2023 study of bigmouth buffalo from Rice Lake National Wildlife Refuge we found that 99.7% (389 of 390) of the extant population hatched prior to 1972 despite annual spawning in Rice Lake. Moreover, recruitment success declined significantly since water control measures were established (1953). We found males arrive to spawning grounds with females but depart later, that both the midpoint and duration of spawn significantly vary across years, and that more massive females of the same age range invest disproportionately more in ovaries. Extensive post-spawn seining revealed bigmouth buffalo young-of-the-year in low numbers, but by mid-to-late summer they were no longer evident having likely succumbed to predation. Overall, these findings thoroughly reveal one of the oldest populations of vertebrate currently known (median age of 79 years as of 2024) and expose the stark vulnerability of a bigmouth buffalo population for which substantial recruitment has not occurred for more than six decades. Multiple lines of evidence indicate that the long-lived bigmouth buffalo is vulnerable, that a precautionary approach is immediately needed, and that the unlimited and unregulated kill-fishery be closed.

The first part of this study was a cross-sectional analysis of the impact of 29 management factors on udder health in organic dairy farms in Switzerland. All 77 farms joined the extension program ‘pro-Q’. As a measure of udder health the theoretical bulk milk somatic cell count (TBMSCC) calculated by the monthly cow composite somatic cell count over a time period of 1 year was chosen. The basic udder health of the farms was determined by TBMSCC during the year prior to the start of the project (mean for all farms = 176 460 cells/ml). In the multivariable analysis, the five factors ‘swiss brown breed’, ‘alpine summer pasturing’, ‘calf feeding with milk from mastitis diseased cows’, ‘hard bedding’ and ‘no post-milking’ remained as significant risk factors on udder health. In the second part of the study, the development of management factors and the udder health situation affected by an extension program after 1 year was investigated. A partial improvement of the management factors on the farms but no overall improvement on udder health and no association between management changes and udder health changes were found. Improvement of udder health was more likely in farms with higher basic TBMSCC than in those farms with less udder health problems at the beginning of the project.

The bivalve mollusc Arctica islandica can live for hundreds of years, and its shell has provided a valuable resource for sclerochronological studies and geochemical analyses for understanding palaeoenvironmental change. Shell specimens recovered from the seabed need to be dated in order to aid sample selection, but existing methods using radiocarbon dating or cross-dating are both costly and time-consuming. We have investigated amino acid geochronology (AAG) as a potential alternative means of providing a less costly and more efficient range-finding method. In order to do this, we have investigated the complex microstructure of the shells, as this may influence the application of AAG. Each of the three microstructural layers of A. islandica have been isolated and their protein degradation examined (amino acid concentration, composition, racemization, and peptide bond hydrolysis). The intra-crystalline protein fraction was successfully extracted following oxidation treatment for 48 h, and high-temperature experiments at 140 °C established coherent breakdown patterns in all three layers, but the inner portion of the outer shell layer (iOSL) was the most appropriate component due to practicalities. Sampling of the iOSL layer in Holocene shells from early and late ontogeny (over 100–400 years) showed that the resolution of AAG is too low in A. islandica for within-shell age resolution. However, analysis of 52 subfossil samples confirmed that this approach could be used to establish a relative geochronology for this biomineral throughout the whole of the Quaternary. In the late Holocene the temporal resolution is ∼1500–2000 years. Relative dating of 160 dredged shells of unknown age was narrowed down using AAG as a range finder, showing that a collection of shells from Iceland and the North Sea covered the middle Holocene, late Holocene, later and post-medieval (1171–1713 CE), and modern day. This study confirms the value of A. islandica as a reliable material for range finding and for dating Quaternary deposits.

In the Firmicutes phylum, GpsB is a membrane associated protein that coordinates peptidoglycan synthesis with cell growth and division. Although GpsB has been studied in several bacteria, the structure, function, and interactome of Staphylococcus aureus GpsB is largely uncharacterized. To address this knowledge gap, we solved the crystal structure of the N-terminal domain of S. aureus GpsB, which adopts an atypical, asymmetric dimer, and demonstrates major conformational flexibility that can be mapped to a hinge region formed by a three-residue insertion exclusive to Staphylococci. When this three-residue insertion is excised, its thermal stability increases, and the mutant no longer produces a previously reported lethal phenotype when overexpressed in Bacillus subtilis. In S. aureus, we show that these hinge mutants are less functional and speculate that the conformational flexibility imparted by the hinge region may serve as a dynamic switch to fine-tune the function of the GpsB complex and/or to promote interaction with its various partners. Furthermore, we provide the first biochemical, biophysical, and crystallographic evidence that the N-terminal domain of GpsB binds not only PBP4, but also FtsZ, through a conserved recognition motif located on their C-termini, thus coupling peptidoglycan synthesis to cell division. Taken together, the unique structure of S. aureus GpsB and its direct interaction with FtsZ/PBP4 provide deeper insight into the central role of GpsB in S. aureus cell division.

The retina is part of the central nervous system specialized for vision. Inherited retinal diseases (IRD) are a group of clinically and genetically heterogenous disorders that lead to progressive vision impairment or blindness. Although each disorder is rare, IRD accumulatively cause blindness in up to 5.5 million individuals worldwide. Currently, the pathophysiological mechanisms of IRD are not fully understood and there are limited treatment options available. Most IRD are caused by degeneration of light-sensitive photoreceptors. Genetic mutations that abrogate the structure and/or function of photoreceptors lead to visual impairment followed by blindness caused by loss of photoreceptors. In healthy retina, photoreceptors structurally and functionally interact with retinal pigment epithelium (RPE) and Müller glia (MG) to maintain retinal homeostasis. Multiple IRD with photoreceptor degeneration as a major phenotype are caused by mutations of RPE- and/or MG-associated genes. Recent studies also reveal compromised MG and RPE caused by mutations in ubiquitously expressed ciliary genes. Therefore, photoreceptor degeneration could be a direct consequence of gene mutations and/or could be secondary to the dysfunction of their interaction partners in the retina. This review summarizes the mechanisms of photoreceptor-RPE/MG interaction in supporting retinal functions and discusses how the disruption of these processes could lead to photoreceptor degeneration, with an aim to provide a unique perspective of IRD pathogenesis and treatment paradigm. We will first describe the biology of retina and IRD and then discuss the interaction between photoreceptors and MG/RPE as well as their implications in disease pathogenesis. Finally, we will summarize the recent advances in IRD therapeutics targeting MG and/or RPE.

BioEYES is a K-12 science outreach program that develops self-sustaining teachers as a replication strategy to address high demand for the program while promoting long-term school partnerships. This paper explores the practices of "model teachers" from multiple grades, who are empowered over a three-year period to deliver BioEYES' hands-on science content autonomously, as compared to the program's standard co-teaching model (BioEYES educator + classroom teacher). The authors found that BioEYES' professional development (PD) workshop, classroom co-teaching experience, and refresher trainings assist teachers in gaining autonomy to teach the program's curricula. In addition, the authors found: 1) a similar effectiveness on student learning across three grade bands, and 2) positive attitude changes about science as a result of the program, regardless if the BioEYES unit was taught by a model teacher or program staff. Further we found that high school model teachers exceeded the performance of BioEYES educators. This observation supports our contention that giving high quality STEM programing that includes multi-level PD to teachers generates the strongest possible outcome. Overall, we characterize the impact and financial investment of BioEYES and describe a PD framework that can be used by outreach providers to deliver content, expand their reach, and sustain school partnerships.

Syndromic autism refers to autism spectrum disorder diagnosed in the context of a known genetic syndrome. The specific manifestations of any one of these syndromic autisms are related to a clinically defined genetic syndrome that can be traced to certain genes and variants, genetic deletions, or duplications at the chromosome level. The genetic mutations or defects in single genes associated with these genetic disorders result in a significant elevation of risk for developing autism relative to the general population and are related to recurrence with inheritance patterns. Additionally, these syndromes are associated with typical behavioral characteristics or phenotypes as well as an increased risk for specific behavioral or psychiatric disorders and clinical findings. Knowledge of these associations helps guide clinicians in identifying potentially treatable conditions that can help to improve the lives of affected patients and their families.

Integration of the Internet of Things (IoT) in the automotive industry has brought benefits as well as security challenges. Significant benefits include enhanced passenger safety and more comprehensive vehicle performance diagnostics. However, current onboard and remote vehicle diagnostics do not include the ability to detect counterfeit parts. A method is needed to verify authentic parts along the automotive supply chain from manufacture through installation and to coordinate part authentication with a secure database. In this study, we develop an architecture for anti-counterfeiting in automotive supply chains. The core of the architecture consists of a cyber-physical trust anchor and authentication mechanisms connected to blockchain-based tracking processes with cloud storage. The key parameters for linking a cyber-physical trust anchor in embedded IoT include identifiers (i.e., serial numbers, special features, hashes), authentication algorithms, blockchain, and sensors. A use case was provided by a two-year long implementation of simple trust anchors and tracking for a coffee supply chain which suggests a low-cost part authentication strategy could be successfully applied to vehicles. The challenge is authenticating parts not normally connected to main vehicle communication networks. Therefore, we advance the coffee bean model with an acoustical sensor to differentiate between authentic and counterfeit tires onboard the vehicle. The workload of secure supply chain development can be shared with the development of the connected autonomous vehicle networks, as the fleet performance is degraded by vehicles with questionable replacement parts of uncertain reliability.

Mowat–Wilson syndrome (MWS) is a rare genetic neurodevelopmental congenital disorder associated with various defects of the zinc finger E-box binding homeobox 2 (ZEB2) gene. The ZEB2 gene is autosomal dominant and encodes six protein domains including the SMAD-binding protein, which functions as a transcriptional corepressor involved in the conversion of neuroepithelial cells in early brain development and as a mediator of trophoblast differentiation. This review summarizes reported ZEB2 gene variants, their types, and frequencies among the 10 exons of ZEB2. Additionally, we summarized their corresponding encoded protein defects including the most common variant, c.2083 C>T in exon 8, which directly impacts the homeodomain (HD) protein domain. This single defect was found in 11% of the 298 reported patients with MWS. This review demonstrates that exon 8 encodes at least three of the six protein domains and accounts for 66% (198/298) of the variants identified. More than 90% of the defects were due to nonsense or frameshift changes. We show examples of protein modeling changes that occurred as a result of ZEB2 gene defects. We also report a novel pathogenic variant in exon 8 in a 5-year-old female proband with MWS. This review further explores other genes predicted to be interacting with the ZEB2 gene and their predicted gene–gene molecular interactions with protein binding effects on embryonic multi-system development such as craniofacial, spine, brain, kidney, cardiovascular, and hematopoiesis.

Bivalves reveal that the subpolar North Atlantic destabilised and shows signs of having crossed a tipping point during the transition into the Little Ice Age.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disabilities and the second most common cause after Down syndrome. FXS is an X-linked disorder due to a full mutation of the CGG triplet repeat of the FMR1 gene which codes for a protein that is crucial in synaptogenesis and maintaining functions of extracellular matrix-related proteins, key for the development of normal neuronal and connective tissue including collagen. In addition to neuropsychiatric and behavioral problems, individuals with FXS show physical features suggestive of a connective tissue disorder including loose skin and joint laxity, flat feet, hernias and mitral valve prolapse. Disturbed collagen leads to hypermobility, hyperextensible skin and tissue fragility with musculoskeletal, cardiovascular, immune and other organ involvement as seen in hereditary disorders of connective tissue including Ehlers–Danlos syndrome. Recently, FMR1 premutation repeat expansion or carrier status has been reported in individuals with connective tissue disorder-related symptoms. We examined a cohort of females with features of a connective tissue disorder presenting for genetic services using next-generation sequencing (NGS) of a connective tissue disorder gene panel consisting of approximately 75 genes. In those females with normal NGS testing for connective tissue disorders, the FMR1 gene was then analyzed using CGG repeat expansion studies. Three of thirty-nine females were found to have gray zone or intermediate alleles at a 1:13 ratio which was significantly higher (p < 0.05) when compared with newborn females representing the general population at a 1:66 ratio. This association of connective tissue involvement in females with intermediate or gray zone alleles reported for the first time will require more studies on how the size variation may impact FMR1 gene function and protein directly or in relationship with other susceptibility genes involved in connective tissue disorders.

The natural element aluminum possesses a number of unique biochemical and biophysical properties that make this highly neurotoxic species deleterious towards the structural integrity, conformation, reactivity and stability of several important biomolecules. These include aluminum’s (i) small ionic size and highly electrophilic nature, having the highest charge density of any metallic cation with a Z2/r of 18 (ionic charge +3, radius 0.5 nm); (ii) inclination to form extremely stable electrostatic bonds with a tendency towards covalency; (iii) ability to interact irreversibly and/or significantly slow down the exchange-rates of complex aluminum–biomolecular interactions; (iv) extremely dense electropositive charge with one of the highest known affinities for oxygen-donor ligands such as phosphate; (v) presence as the most abundant metal in the Earth’s biosphere and general bioavailability in drinking water, food, medicines, consumer products, groundwater and atmospheric dust; and (vi) abundance as one of the most commonly encountered intracellular and extracellular metallotoxins. Despite aluminum’s prevalence and abundance in the biosphere it is remarkably well-tolerated by all plant and animal species; no organism is known to utilize aluminum metabolically; however, a biological role for aluminum has been assigned in the compaction of chromatin. In this Communication, several examples are given where aluminum has been shown to irreversibly perturb and/or stabilize the natural conformation of biomolecules known to be important in energy metabolism, gene expression, cellular homeostasis and pathological signaling in neurological disease. Several neurodegenerative disorders that include the tauopathies, Alzheimer’s disease and multiple prion disorders involve the altered conformation of naturally occurring cellular proteins. Based on the data currently available we speculate that one way aluminum contributes to neurological disease is to induce the misfolding of naturally occurring proteins into altered pathological configurations that contribute to the neurodegenerative disease process.

Parthenogenesis, reproduction without fertilization, is not common in the Chironomidae (Diptera), a family of insects with more than 6,000 described species. Nonetheless, parthenogenetic species and strains have been documented in at least three subfamilies (the Chironominae, Orthocladiinae, and Telmatogoninae), spanning 17 genera and ~30 species. One such species, Paratanytarsus laccophilus Edwards 1929, is known to be parthenogenetic in a small portion of its range in Finland, with most other European populations of this species showing evidence of sexual reproduction. We present evidence of parthenogenetic populations from the Paratanytarsus laccophilus species group in the Nearctic, specifically a High Arctic site near Utqiaġvik (formerly Barrow), Alaska. During May-July of 2015 and 2016, we sampled emerging adult chironomids and pupal exuviae daily to document insect emergence phenologies. Across 15 local populations, all 623 pupal exuviae collected from the P. laccophilus species group were female. Larvae reared from two populations under controlled temperature treatments emerged as female adults (N=37). When isolated, these reared female adults oviposited, and eggs hatched successfully. These progeny were reared for another 12-13 days, reaching second instar larvae when they were preserved at the end of our field season. Taken together, this evidence strongly indicates parthenogenesis from the P. laccophilus species group at this location. This species was not previously documented at Utqiaġvik. Although parthenogenetic, their emergence at this location was highly synchronized. In the harsh environment of arctic Alaska, the fitness rewards of parthenogenesis are likely great. Indeed, chironomid parthenogenesis in the northern hemisphere is most commonly documented from far-northern extremes and in extreme habitats.