Search

Well-preserved specimens of a new species of arthrodiran placoderm, Groenlandaspis howittensis sp. nov. (Middle Devonian of Victoria, Australia), reveals previously unknown information on the dermal skeleton, body-shape and dentition of the wide-spread genus Groenlandaspis. The new material includes dual pineal plates, extrascapular plates, and cheek bones showing the presence of cutaneous sensory organs. The anterior supragnathal, usually a paired element in arthrodires, is a fused median bone in G. howittensis sp. nov. It is positioned anterior to the occlusion of the mouth between the lower jaw (infragnathals) and upper jaw (posterior supragnathals) bones, indicating a specialised feeding mechanism and broadening the known diversity of placoderm dental morphologies. G. howittensis sp. nov. differs from all other groenlandaspidids by a less pronounced posterior expansion of the nuchal plate; the shape of the posterior dorsolateral plate and the presence of a short accessory canal on the anterior dorsolateral plate. A new phylogenetic analysis positions Groenlandaspididae in a monophyly with the phlyctaeniid families Arctolepidae and Arctaspididae, however, the specific intrarelationships of groenlandaspidids remain poorly resolved.

Mitochondrial DNA (mtDNA) deletion mutations cause many human diseases and are linked to age-induced mitochondrial dysfunction. Mapping the mutation spectrum and quantifying mtDNA deletion mutation frequency is challenging with next-generation sequencing methods. We hypothesized that long-read sequencing of human mtDNA across the lifespan would detect a broader spectrum of mtDNA rearrangements and provide a more accurate measurement of their frequency. We employed nanopore Cas9-targeted sequencing (nCATS) to map and quantitate mtDNA deletion mutations and develop analyses that are fit-for-purpose. We analyzed total DNA from vastus lateralis muscle in 15 males ranging from 20 to 81 years of age and substantia nigra from three 20-year-old and three 79-year-old men. We found that mtDNA deletion mutations detected by nCATS increased exponentially with age and mapped to a wider region of the mitochondrial genome than previously reported. Using simulated data, we observed that large deletions are often reported as chimeric alignments. To address this, we developed two algorithms for deletion identification which yield consistent deletion mapping and identify both previously reported and novel mtDNA deletion breakpoints. The identified mtDNA deletion frequency measured by nCATS correlates strongly with chronological age and predicts the deletion frequency as measured by digital PCR approaches. In substantia nigra, we observed a similar frequency of age-related mtDNA deletions to those observed in muscle samples, but noted a distinct spectrum of deletion breakpoints. NCATS-mtDNA sequencing allows the identification of mtDNA deletions on a single-molecule level, characterizing the strong relationship between mtDNA deletion frequency and chronological aging.

Beta-guanidinopropionic acid (GPA) is a creatine analog suggested as a treatment for hypertension, diabetes, and obesity, which manifest primarily in older adults. A notable side effect of GPA is the induction of mitochondrial DNA deletion mutations. We hypothesized that mtDNA deletions contribute to muscle aging and used the mutation promoting effect of GPA to examine the impact of mtDNA deletions on muscles with differential vulnerability to aging. Rats were treated with GPA for up to 4 months starting at 14 or 30 months of age. We examined quadriceps and adductor longus muscles as the quadriceps exhibits profound age-induced deterioration, while adductor longus is maintained. GPA decreased body and muscle mass and mtDNA copy number while increasing mtDNA deletion frequency. The interactions between age and GPA treatment observed in the quadriceps were not observed in the adductor longus. GPA had negative mitochondrial effects in as little as 4 weeks. GPA treatment exacerbated mtDNA deletions and muscle aging phenotypes in the quadriceps, an age-sensitive muscle, while the adductor longus was spared. GPA has been proposed for use in age-associated diseases, yet the pharmacodynamics of GPA differ with age and include the detrimental induction of mtDNA deletions, a mitochondrial genotoxic stress that is pronounced in muscles that are most vulnerable to aging. Further research is needed to determine if the proposed benefits of GPA on hypertension, diabetes, and obesity outweigh the detrimental mitochondrial and myopathic side effects.

The COVID-19 pandemic has highlighted many challenges undergraduate students face including their ability to manage stress. Poor stress management can contribute to poor academic performance and health outcomes; better wellness habits and stress reduction go hand-in-hand, as improved wellness habits reduce overall stress and expand positive stress management strategies. This article describes the design of a short wellness intervention for STEM classes and its evaluation after implementation in five chemistry and biology courses that span the four years of a biochemistry degree. This intervention, composed of a short, in-class presentation and an associated supplemental resource handout, presents students with information on five wellness areas: sleep, nutrition, water intake, exercise, and meditation and mindfulness. Students were surveyed at three points (once preintervention and twice postintervention) in one semester and asked to report their perceived stress, current wellness habits, and overall perception of the intervention. Notably, the majority of students (89%) thought the intervention should be included in other courses. The importance of completing the intervention in class was underscored by the small number of students (19%) who reported accessing the additional resources provided outside of class. Student wellness habits did not dramatically shift postintervention, but this study garnered insights into the barriers students face when attempting to change their wellness behavior. Overwhelmingly students reported that academic workload was the dominant factor hindering positive wellness change. The intervention materials, including a suggested script, are shared, and data-supported recommendations for implementation in other courses and institutions are provided.

The mitochondrial genome (mtDNA) is an important source of disease-causing genetic variability, but existing sequencing methods limit understanding, precluding phased measurement of mutations and clear detection of large sporadic deletions. We adapted a method for amplification-free sequence enrichment using Cas9 cleavage to obtain full length nanopore reads of mtDNA. We then utilized the long reads to phase mutations in a patient with an mtDNA-linked syndrome and demonstrated that this method can map age-induced mtDNA deletions. We believe this method will offer deeper insight into our understanding of mtDNA variation.

Mitochondrial dysfunction is frequently associated with impairment in metabolic homeostasis and insulin action, and is thought to underlie cellular aging. However, it is unclear whether mitochondrial dysfunction is a cause or consequence of insulin resistance in humans. To determine the impact of intrinsic mitochondrial dysfunction on metabolism and insulin action, we performed comprehensive metabolic phenotyping of the polymerase gamma (PolG) D257A "mutator" mouse, a model known to accumulate supraphysiological mitochondrial DNA (mtDNA) point mutations. We utilized the heterozygous PolG mutator mouse (PolG+/mut ) because it accumulates mtDNA point mutations ~ 500-fold > wild-type mice (WT), but fails to develop an overt progeria phenotype, unlike PolGmut/mut animals. To determine whether mtDNA point mutations induce metabolic dysfunction, we examined male PolG+/mut mice at 6 and 12 months of age during normal chow feeding, after 24-hr starvation, and following high-fat diet (HFD) feeding. No marked differences were observed in glucose homeostasis, adiposity, protein/gene markers of metabolism, or oxygen consumption in muscle between WT and PolG+/mut mice during any of the conditions or ages studied. However, proteomic analyses performed on isolated mitochondria from 12-month-old PolG+/mut mouse muscle revealed alterations in the expression of mitochondrial ribosomal proteins, electron transport chain components, and oxidative stress-related factors compared with WT. These findings suggest that mtDNA point mutations at levels observed in mammalian aging are insufficient to disrupt metabolic homeostasis and insulin action in male mice.

The age-induced, exponential accumulation of mitochondrial DNA (mtDNA) deletion mutations contributes to muscle fiber loss. The causes of these mutations are not known. Systemic inflammation is associated with decreased muscle mass in older adults and is implicated in the formation of sporadic mtDNA deletions. Macrophage migration inhibitory factor knockout (MIF-KO) mice are long-lived with decreased inflammation. We hypothesized that aged MIF-KO mice would have lower mtDNA deletion frequencies and fewer electron transport chain (ETC) deficient fibers. We measured mtDNA copy number and mutation frequency as well as the number and length of ETC deficient fibers in 22-month old MIF-KO and F2 hybrid control mice. We also measured mtDNA copy number and deletion frequency in female UM-HET3 mice, a strain whose lifespan matches the MIF-KO mice. We did not observe a significant effect of MIF ablation on muscle mtDNA deletion frequency. There was a significantly lower mtDNA copy number in the MIF-KO mice and the lifespan-matched UM-HET3 mice compared to the F2 hybrids, suggesting the importance of genetic background in mtDNA copy number control. Our data do not support a definitive role for MIF in age-induced mtDNA deletions.

The practice of combining imaging modalities emerged from the quest to discover novel insights into the structure and function of various samples. As these techniques merge, so do their names, creating a plethora of unique acronyms that can seem like an alphabet soup. Highlighted here are several notable combination techniques such as Correlative Light and Electron Microscopy (CLEM), Atomic Force Microscopy (AFM), Total Internal Reflection Fluorescence (TIRF), Selective Plane Illumination Microscopy (SPIM), and Two-Photon Excited Fluorescence – Second Harmonic Generation (TPEF-SHG). Each of these methods extends beyond the capabilities of their individual components to significantly advance scientific research. This article, Part 3 of our "Alphabet Soup of Microscopy" series, seeks to distinguish these popular combination techniques from their standalone predecessors. [ABSTRACT FROM AUTHOR]

Abstract Tumor hypoxia drives resistance to many cancer therapies, including radiotherapy and chemotherapy. Methods that increase tumor oxygen pressures, such as hyperbaric oxygen therapy and microbubble infusion, are utilized to improve the responses to current standard‐of‐care therapies. However, key obstacles remain, in particular delivery of oxygen at the appropriate dose and with optimal pharmacokinetics. Toward overcoming these hurdles, gas‐entrapping materials (GeMs) that are capable of tunable oxygen release are formulated. It is shown that injection or implantation of these materials into tumors can mitigate tumor hypoxia by delivering oxygen locally and that these GeMs enhance responsiveness to radiation and chemotherapy in multiple tumor types. This paper also demonstrates, by comparing an oxygen (O2)‐GeM to a sham GeM, that the former generates an antitumorigenic and immunogenic tumor microenvironment in malignant peripheral nerve sheath tumors. Collectively the results indicate that the use of O2‐GeMs is promising as an adjunctive strategy for the treatment of solid tumors.

Youth represent a large proportion of new HIV infections worldwide, yet their utilization of HIV testing and counseling (HTC) remains low. Using the post-intervention, cross-sectional, population-based household survey done in 2011 as part of HPTN 043/NIMH Project Accept, a cluster-randomized trial of community mobilization and mobile HTC in South Africa (Soweto and KwaZulu Natal), Zimbabwe, Tanzania and Thailand, we evaluated age-related differences among socio-demographic and behavioral determinants of HTC in study participants by study arm, site, and gender. A multivariate logistic regression model was developed using complete individual data from 13,755 participants with recent HIV testing (prior 12 months) as the outcome. Youth (18-24 years) was not predictive of recent HTC, except for high-risk youth with multiple concurrent partners, who were less likely (aOR 0.75; 95% CI 0.61-0.92) to have recently been tested than youth reporting a single partner. Importantly, the intervention was successful in reaching men with site specific success ranging from aOR 1.27 (95% CI 1.05-1.53) in South Africa to aOR 2.30 in Thailand (95% CI 1.85-2.84). Finally, across a diverse range of settings, higher education (aOR 1.67; 95% CI 1.42, 1.96), higher socio-economic status (aOR 1.21; 95% CI 1.08-1.36), and marriage (aOR 1.55; 95% CI 1.37-1.75) were all predictive of recent HTC, which did not significantly vary across study arm, site, gender or age category (18-24 vs. 25-32 years).

Inflammation is a primary component of the central nervous system injury response. Traumatic brain and spinal cord injury are characterized by a pronounced microglial response to damage, including alterations in microglial morphology and increased production of reactive oxygen species (ROS). The acute activity of microglia may be beneficial to recovery, but continued inflammation and ROS production is deleterious to the health and function of other cells. Microglial nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), mitochondria, and changes in iron levels are three of the most common sources of ROS. All three play a significant role in post-traumatic brain and spinal cord injury ROS production and the resultant oxidative stress. This review will evaluate the current state of therapeutics used to target these avenues of microglia-mediated oxidative stress after injury and suggest avenues for future research.

The use of fluorescence in imaging has been a pivotal factor in advancing our scientific understanding. As microscopy continues to evolve, the terminology used to describe these techniques becomes increasingly complex, often resulting in a bewildering array of acronyms that resemble alphabet soup. Among the most prominent acronyms are those associated with advanced fluorescence microscopy techniques: Fluorescence Loss in Photobleaching (FLIP), Fluorescence Localization after Photobleaching (FLAP), Fluorescence Recovery after Photobleaching (FRAP), Förster Resonance Energy Transfer (FRET), and Fluorescence Lifetime Imaging Microscopy (FLIM). Each of these methods provides invaluable insights into molecular dynamics and interactions within living cells and tissues. This article, Part 2 of the Alphabet Soup of Microscopy series, aims to clarify these widely used fluorescence microscopy techniques and to illuminate their contributions to our understanding of cellular processes. [ABSTRACT FROM AUTHOR]

Abstract A novel nanoparticle‐polymer composite is proposed, named inverse nanocomposites in this work. First, a rigid percolating scaffold of nanoparticles is formed, which is filled with a matrix and then polymerized. Targeted for use in thin‐film applications, these mesoporous nanoparticle scaffolds are prepared by combining the sol–gel chemistry of functionalized silanes with nanoparticles in dispersions. The nanoparticle coatings have high porosity, low density, good adhesion to the substrate, and interesting non‐classical properties, such as absorbency of highly viscous fluids. The porosity, which can be adjusted by changing the composition and preparation parameters, reaches 75%. The porous scaffold can be infiltrated with various fluids, including acrylic and epoxy monomers and even highly viscous pressure‐sensitive adhesives. If the monomers are polymerized after imbibition, the inverse nanocomposite is formed, consisting of a percolating particle network surrounded by a polymeric binder. Hence, the morphology comprises an interpenetrating system of two co‐continuous phases and not merely particles dispersed in a polymeric phase, as is typical for conventionally prepared nanocomposites.