A distributed, high-channel-count, implanted bidirectional system for restoration of somatosensation and myoelectric control.

Objective. We intend to chronically restore somatosensation and provide high-fidelity myoelectric control for those with limb loss via a novel, distributed, high-channel-count, implanted system.Approach.We have developed the implanted Somatosensory Electrical Neurostimulation and Sensing (iSens®) system to support peripheral nerve stimulation through up to 64, 96, or 128 electrode contacts with myoelectric recording from 16, 8, or 0 bipolar sites, respectively. The rechargeable central device has Bluetooth® wireless telemetry to communicate to external devices and wired connections for up to four implanted satellite stimulation or recording devices. We characterized the stimulation, recording, battery runtime, and wireless performance and completed safety testing to support its use in human trials.Results.The stimulator operates as expected across a range of parameters and can schedule multiple asynchronous, interleaved pulse trains subject to total charge delivery limits. Recorded signals in saline show negligible stimulus artifact when 10 cm from a 1 mA stimulating source. The wireless telemetry range exceeds 1 m (direction and orientation dependent) in a saline torso phantom. The bandwidth supports 100 Hz bidirectional update rates of stimulation commands and data features or streaming select full bandwidth myoelectric signals. Preliminary first-in-human data validates the bench testing result.Significance.We developed, tested, and clinically implemented an advanced, modular, fully implanted peripheral stimulation and sensing system for somatosensory restoration and myoelectric control. The modularity in electrode type and number, including distributed sensing and stimulation, supports a wide variety of applications; iSens® is a flexible platform to bring peripheral neuromodulation applications to clinical reality. ClinicalTrials.gov ID NCT04430218.

Purine salvage promotes treatment resistance in H3K27M-mutant diffuse midline glioma.

BACKGROUND: Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are a fatal form of brain cancer. These tumors often carry a driver mutation on histone H3 converting lysine 27 to methionine (H3K27M). DMG-H3K27M are characterized by altered metabolism and resistance to standard of care radiation (RT) but how the H3K27M mediates the metabolic response to radiation and consequent treatment resistance is uncertain. METHODS: We performed metabolomics on irradiated and untreated H3K27M isogenic DMG cell lines and observed an H3K27M-specific enrichment for purine synthesis pathways. We profiled the expression of purine synthesis enzymes in publicly available patient data and our models, quantified purine synthesis using stable isotope tracing, and characterized the in vitro and in vivo response to de novo and salvage purine synthesis inhibition in combination with RT. RESULTS: DMG-H3K27M cells activate purine metabolism in an H3K27M-specific fashion. In the absence of genotoxic treatment, H3K27M-expressing cells have higher relative activity of de novo synthesis and apparent lower activity of purine salvage demonstrated via stable isotope tracing of key metabolites in purine synthesis and by lower expression of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), the rate-limiting enzyme of purine salvage into IMP and GMP. Inhibition of de novo guanylate synthesis radiosensitized DMG-H3K27M cells in vitro and in vivo. Irradiated H3K27M cells upregulated HGPRT expression and hypoxanthine-derived guanylate salvage but maintained high levels of guanine-derived salvage. Exogenous guanine supplementation decreased radiosensitization in cells treated with combination RT and de novo purine synthesis inhibition. Silencing HGPRT combined with RT markedly suppressed DMG-H3K27M tumor growth in vivo. CONCLUSIONS: Our results indicate that DMG-H3K27M cells rely on highly active purine synthesis, both from the de novo and salvage synthesis pathways. However, highly active salvage of free purine bases into mature guanylates can bypass inhibition of the de novo synthetic pathway. We conclude that inhibiting purine salvage may be a promising strategy to overcome treatment resistance in DMG-H3K27M tumors.

Sedation with dexmedetomidine-butorphanol or xylazine-butorphanol continuous intravenous infusions during unilateral ovariectomy in standing donkeys.

BACKGROUND: Intravenous infusions of alpha-2 adrenoceptor sedatives and opioids can potentially facilitate surgery in donkeys while standing. Literature on this subject matter is scant. OBJECTIVES: Evaluation of efficacy of sedation from α2 -adrenoceptors (dexmedetomidine or xylazine) and butorphanol during ovariectomy in standing donkeys. STUDY DESIGN: Randomised, masked in vivo experiment. METHODS: Thirteen female donkeys were sedated with butorphanol (0.05 mg/kg bwt followed by 0.05 mg/kg bwt/h) IV. Concomitantly, 6 of the 13 jennies were sedated with dexmedetomidine 2.5 mcg/kg bwt followed by 2.5 mcg/kg bwt/h (Dex-B group), while seven jennies were sedated with xylazine 0.5 mg/kg bwt followed by 0.5 mg/kg bwt/h (Xyl-B group). A line block of the left flank and an infiltration block around uterine ligament were performed with lidocaine. While the jennies underwent ovariectomies standing, sedation scores and head height above ground were assessed at 2 and 10 min after sedative boluses and every 10 min thereafter. If sedation was too light or too deep, the dose of dexmedetomidine or xylazine was increased or decreased by 25% of the original infusion rate, while butorphanol infusion rate was constant. Physiological parameters were measured. Normally distributed data were compared using the two-sample t test while repeatedly measured data were tested for differences between and within groups using repeated measures analysis of variance (ANOVA) by ranks followed by a Wilcoxon test with Tukey Honest Significant Difference for multiple testing. Statistical significance was set at p < 0.05. RESULTS: Both Dex-B and Xyl-B caused moderate to marked sedation adequate for ovariectomy in donkeys. Evident sedation was absent by 60 min of termination of infusions. No adverse physiological effects were observed. MAIN LIMITATIONS: Study on ovariectomy cases only, no pharmacokinetic profiling. CONCLUSIONS: Dexmedetomidine or xylazine and butorphanol sedation is feasible for ovariectomy in standing donkeys.

GTP Signaling Links Metabolism, DNA Repair, and Responses to Genotoxic Stress.

How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a guanine nucleotide-binding protein, which promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes nonhomologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard-of-care genotoxic treatments. The GTP-Rac1-PP5-Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in nonmalignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment. SIGNIFICANCE: A newly described GTP-dependent signaling axis is an unexpected link between nucleotide metabolism and DNA repair. Disrupting this pathway can overcome cancer resistance to genotoxic therapy while augmenting it can mitigate genotoxic injury of normal tissues. This article is featured in Selected Articles from This Issue, p. 5.

Adaptive rewiring of purine metabolism promotes treatment resistance in H3K27M-mutant diffuse midline glioma.

Background: Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are a fatal form of brain cancer. These tumors often carry a driver mutation on histone H3 converting lysine 27 to methionine (H3K27M). DMG-H3K27M are characterized by altered metabolism and resistance to standard of care radiation (RT), but how the H3K27M mediates the metabolic response to radiation and consequent treatment resistance is uncertain. Methods: We performed metabolomics on irradiated and untreated H3K27M isogenic DMG cell lines and observed an H3K27M-specific enrichment for purine synthesis pathways. We profiled the expression of purine synthesis enzymes in publicly available patient data and in our models, quantified purine synthetic flux using stable isotope tracing, and characterized the in vitro and in vivo response to de novo and salvage purine synthesis inhibition in combination with RT. Results: DMG-H3K27M cells activate purine metabolism in an H3K27M-specific fashion. In the absence of genotoxic treatment, H3K27M-expressing cells have higher relative activity of de novosynthesis and lower activity of purine salvage due to decreased expression of the purine salvage enzymes. Inhibition of de novo synthesis radiosensitized DMG-H3K27M cells in vitro and in vivo. Irradiated H3K27M cells adaptively upregulate purine salvage enzyme expression and pathway activity. Silencing the rate limiting enzyme in purine salvage, hypoxanthine guanine phosphoribosyl transferase (HGPRT) when combined with radiation markedly suppressed DMG-H3K27M tumor growth in vivo. Conclusions: H3K27M expressing cells rely on de novo purine synthesis but adaptively upregulate purine salvage in response to RT. Inhibiting purine salvage may help overcome treatment resistance in DMG-H3K27M tumors.

Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways.

Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.

Boldness, activity, and aggression: Insights from a large-scale study in Baltic salmon (Salmo salar L).

Atlantic salmon (Salmo salar) display high levels of agonistic behavior in aquaculture farms, resulting in fin damage and chronic stress. Aggression affects fish growth and performance negatively, and presents a serious welfare problem. Indeed, it would be beneficial to identify, separate or exclude overly aggressive individuals. Research on behavioral syndromes suggests that aggressive behavior may correlate with other behavioral traits, such as boldness and locomotory activity. We aimed to develop a high-throughput method to quantify and predict aggressive behavior of individual parr in hatchery-reared Baltic salmon (Salmo salar L.). We screened approximately 2000 parr in open field (OF) and mirror image stimulation (MIS) tests. We extracted seven variables from video tracking software for each minute of the tests; distance moved and duration moving (activity), the duration in and number of entries to the center of the arena (boldness), the distance moved in and duration spent in the area adjacent to the mirror during the MIS test (aggressiveness) and head direction (lateralization). To investigate the relationship between activity, boldness and aggression we first correlated the first six variables to one another. Second, we assigned individuals to high, medium, low or zero aggression groups based on the MIS test and quantified activity and boldness in each group. Third, we analyzed whether the fish viewed the mirror with the left or right eye. Our results show that medium and low aggressive fish were the most active, while highly aggressive fish showed average activity. Aggressive groups did not differ in boldness. Activity and boldness were positively correlated. Finally, we detected a preference for fish to view the mirror with the left eye. We conclude that aggressiveness cannot be predicted from the results of the OF test alone but that the MIS test can be used for large-scale individual aggression profiling of juvenile salmon.

Aperiodic Neural Activity is a Better Predictor of Schizophrenia than Neural Oscillations.

Diagnosis and symptom severity in schizophrenia are associated with irregularities across neural oscillatory frequency bands, including theta, alpha, beta, and gamma. However, electroencephalographic signals consist of both periodic and aperiodic activity characterized by the (1/fX) shape in the power spectrum. In this paper, we investigated oscillatory and aperiodic activity differences between patients with schizophrenia and healthy controls during a target detection task. Separation into periodic and aperiodic components revealed that the steepness of the power spectrum better-predicted group status than traditional band-limited oscillatory power in classification analysis. Aperiodic activity also outperformed the predictions made using participants' behavioral responses. Additionally, the differences in aperiodic activity were highly consistent across all electrodes. In sum, compared to oscillations the aperiodic activity appears to be a more accurate and more robust way to differentiate patients with schizophrenia from healthy controls.

GTP signaling links metabolism, DNA repair, and responses to genotoxic stress.

How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a G protein, that promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes non-homologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard of care genotoxic treatments. The GTP-Rac1-PP5-Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in non-malignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment.

Utility of Teledermatology in the Diagnosis of Loose Anagen Syndrome.

Introduction: Teledermatology has been shown to improve efficiency and reduce barriers to care for patients. However, teledermatology is limited by the inability to perform diagnostic tests. With proper planning, teletrichoscopy can be utilized with teledermatology to evaluate patients with hair loss. Case Presentation: Diagnosis of this patient was made using images taken during the televisit, including scalp images taken by the patient using a handheld microscope and images of the hair roots taken by her referring doctor. Conclusion: Hair tests that can be conducted during teledermatology visits include a self-performed pull test, measurement of the thickness of the ponytail, measurement of the distance from the hairline to the glabella, and evaluation of the shedding scale. These tests, in addition to mobile applications for imaging or low-cost handheld microscopes, can be utilized to virtually evaluate patients with hair loss.

Using Stable Isotopes to Determine Natal Origin and Feeding Habits of the Army Cutworm Moth, Euxoa auxiliaris (Lepidoptera: Noctuidae).

The army cutworm, Euxoa auxiliaris (Grote), is a migratory noctuid that is both an agricultural pest and an important late-season food source for grizzly bears, Ursus arctos horribilis (Linnaeus, Carnivora: Ursidae), within the Greater Yellowstone Ecosystem. Beyond the confirmation of the moths' seasonal, elevational migration in the mid-1900s, little else has been documented about their migratory patterns. To address this missing ecological component, we examined (1) migratory routes during their spring and fall migratory periods throughout their natal range, the Great Plains, and (2) natal origin at two of their summering ranges using stable hydrogen (δ2H) analyses of wings from samples collected within the areas of interest. Stable carbon (δ13C) and stable nitrogen (δ15N) analyses of wings were used to evaluate larval feeding habits of the migrants and agricultural intensity of natal origin sites, respectively. Results suggest that, rather than migrating exclusively east to west, army cutworm moths are also migrating north to south during their spring migration. Moths did not exhibit natal origin site fidelity when returning to the Great Plains. Migrants collected from the Absaroka Range had the highest probability of natal origin in Alberta, British Columbia, Saskatchewan, the most southern region of the Northwest Territories, and second highest probability of origin in Montana, Wyoming, and Idaho. Migrants collected in the Lewis Range had the highest probability of origin in the same provinces of Canada. Results suggest that migrants of the Absaroka Range fed exclusively on C3 plants as larvae and rarely fed in heavily fertilized agroecosystems.

The racist origins, racialist connotations, and purity assumptions of the concept of "admixture" in human evolutionary genetics.

The concept of admixture is currently widely being used, both in population genetics research and in DNA ancestry testing discourse. It is assumed to describe the process of gene flow between 2 previously distinct populations that eventually become admixed because of this flow. The concept per se does not require pure or unadmixed populations; the changes are relative and what matters is the level of admixture before and after the event under consideration. However, in this paper, we argue that the concept of admixture as currently used assumes the existence of pure or unadmixed categories. These do not need to have actually existed but to be able to exist in principle. We argue that this is a problematic notion that accrues from the racialist origins of the term admixture, which, as a result, is based on assumptions about purity. We suggest that scientists should be very cautious in their use of this term, especially in science education and communication. We also suggest that the term admixture should be better replaced by terms denoting similarity rather than difference.

Efficacy and Safety of Native and Recombinant Zona Pellucida Immunocontraceptive Vaccines Formulated with Non-Freund's Adjuvants in Donkeys.

This study aimed to test zona pellucida (ZP) vaccines' immunocontraceptive efficacy and safety when formulated with non-Freund's adjuvant (6% Pet Gel A and 500 Μg Poly(I:C)). Twenty-four jennies were randomly assigned to three treatment groups: reZP (n = 7) received three doses of recombinant ZP vaccine; pZP (n = 9) received two doses of native porcine ZP; and Control group (n = 8) received two injections of placebo. Jennies were monitored weekly via transrectal ultrasonography and blood sampling for serum progesterone profiles and anti-pZP antibody titres. In addition, adverse effects were inspected after vaccination. Thirty-five days after the last treatment, jacks were introduced to each group and rotated every 28 days. Vaccination with both pZP and reZP was associated with ovarian shutdown in 44% (4/9) and 71% (4/7) of jennies, 118 ± 33 and 91 ± 20 days after vaccination, respectively (p > 0.05). Vaccination delayed the chances of a jenny becoming pregnant (p = 0.0005; Control, 78 ± 31 days; pZP, 218 ± 69 days; reZP, 244 ± 104 days). Anti-pZP antibody titres were elevated in all vaccinated jennies compared to Control jennies (p < 0.05). In addition, only mild local injection site reactions were observed in the jennies after treatment. In conclusion, ZP vaccines formulated with non-Freund's adjuvant effectively controlled reproduction in jennies with only minor localised side effects.

The third-way third wave and the enduring appeal of bioexceptionalism.

We may induce from a longue durée examination of Anglo-American History of Biology that the impulse to reject reduc - tionism persists and will continue to percolate cyclically. This impulse I deem "bioexceptionalism": an intuition, stance, attitude, or activating metaphor that the study of living beings requires explanations in addition to exclusively bottom-up causal explanations and the research programs constructed upon that bottom-up philosophical foundation by non-organismal biologists, biochemists, and biophysicists - the explanations, in other words, that Wadding - ton (1977) humorously termed the "Conventional Wisdom of the Dominant Group, or cowdung." Bioexceptionalism might indicate an ontological assertion, like vitalism. Yet most often in the last century, it has been defined by a variety of methodological or even sociological positions. On three occasions in the interval from the late nineteenth century to the present, a small but significant group of practicing biologists and allies in other research disciplines in the UK and US adopted a species of bioexceptionalism, rejecting the dominant explanatory philosophy of reductionistic mechanism. Yet they also rejected the vitalist alternative. We can refer to their subset of bioexceptionalism as a "Third-Way" approach, though participants at the time called it by a variety of names, including "organicism." Today's appeals to a Third-Way are but the latest eruption of this older dissensus and retain at least heuristic value apart from any explanatory success.