Quantifying the effects of exceptional fossil preservation on the global availability of phylogenetic data in deep time.

Fossil deposits with exceptional preservation ("lagerstätten") provide important details not typically preserved in the fossil record, such that they hold an outsized influence on our understanding of biodiversity and evolution. In particular, the potential bias imparted by this so-called "lagerstätten effect" remains a critical, but underexplored aspect of reconstructing evolutionary relationships. Here, we quantify the amount of phylogenetic information available in the global fossil records of 1,327 species of non-avian theropod dinosaurs, Mesozoic birds, and fossil squamates (e.g., lizards, snakes, mosasaurs), and then compare the influence of lagerstätten deposits on phylogenetic information content and taxon selection in phylogenetic analyses to other fossil-bearing deposits. We find that groups that preserve a high amount of phylogenetic information in their global fossil record (e.g., non-avian theropods) are less vulnerable to a "lagerstätten effect" that leads to disproportionate representation of fossil taxa from one geologic unit in an evolutionary tree. Additionally, for each taxonomic group, we find comparable amounts of phylogenetic information in lagerstätten deposits, even though corresponding morphological character datasets vary greatly. Finally, we unexpectedly find that ancient sand dune deposits of the Late Cretaceous Gobi Desert of Mongolia and China exert an anomalously large influence on the phylogenetic information available in the squamate fossil record, suggesting a "lagerstätten effect" can be present in units not traditionally considered lagerstätten. These results offer a phylogenetics-based lens through which to examine the effects of exceptional fossil preservation on biological patterns through time and space, and invites further quantification of evolutionary information in the rock record.

The effect of acute exercise on objectively measured sleep and cognition in older adults.

Background: Exercise can improve cognition in aging, however it is unclear how exercise influences cognition, and sleep may partially explain this association. The current study aimed to investigate whether objectively measured sleep mediates the effect of an acute exercise intervention on cognition in older adults. Methods: Participants were 30 cognitively unimpaired, physically active older adults (69.2 ± 4.3 years) with poor sleep (determined via self-report). After a triple baseline cognitive assessment to account for any natural fluctuation in cognitive performance, participants completed either a single bout of 20-minutes of high intensity exercise on a cycle ergometer, or a control condition, in a cross-over trial design. Cognition was measured immediately post-intervention and the following day, and sleep (total sleep time, sleep onset latency, sleep efficiency, % of rapid eye movement sleep, light sleep and deep sleep) was characterized using WatchPAT™ at baseline (5 nights) and measured for one night after both exercise and control conditions. Results: Results showed no effect of the exercise intervention on cognition immediately post-intervention, nor an effect of acute exercise on any sleep variable. There was no mediating effect of sleep on associations between exercise and cognition. However, a change from baseline to post-intervention in light sleep and deep sleep did predict change in episodic memory at the ~24 h post-intervention cognitive assessment, regardless of intervention condition. Discussion: There was no effect of acute high intensity exercise on sleep or cognition in the current study. However, results suggest that associations between sleep and cognition may exist independently of exercise in our sample. Further research is required, and such studies may aid in informing the most effective lifestyle interventions for cognitive health.

Blood-Flow Restriction Is Associated With More Even Pacing During High-Intensity Cycling.

PURPOSE: This study examined the influence of blood-flow restriction (BFR) on the distribution of pace, physiological demands, and perceptual responses during self-paced cycling. METHODS: On separate days, 12 endurance cyclists/triathletes were instructed to produce the greatest average power output during 8-minute self-paced cycling trials with BFR (60% arterial occlusion pressure) or without restriction (CON). Power output and cardiorespiratory variables were measured continuously. Perceived exertion, muscular discomfort, and cuff pain were recorded every 2 minutes. RESULTS: Linear regression analysis of the power output slope was statistically significant (ie, deviated from the intercept) for CON (2.7 [3.2] W·30 s-1; P = .009) but not for BFR (-0.1 [3.1] W·30 s-1; P = .952). Absolute power output was ∼24% (12%) lower at all time points (P < .001) during BFR compared with CON. Oxygen consumption (18% [12%]; P < .001), heart rate (7% [9%]; P < .001), and perceived exertion (8% [21%]; P = .008) were reduced during BFR compared with CON, whereas muscular discomfort (25% [35%]; P = .003) was greater. Cuff pain was rated as "strong" (5.3 [1.8] au; 0-10 scale) for BFR. CONCLUSION: Trained cyclists adopted a more even distribution of pace when BFR was applied compared with a negative distribution during CON. By presenting a unique combination of physiological and perceptual responses, BFR is a useful tool to understand how the distribution of pace is self-regulated.

ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma.

Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA-mutations showed increased sensitivity to ONC201, while those harboring TP53-mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992.

ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma.

Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA mutations showed increased sensitivity to ONC201, whereas those harboring TP53 mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992. SIGNIFICANCE: PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib.

The femora of Drepanosauromorpha (Reptilia: Diapsida): Implications for the functional evolution of the thigh of Sauropsida.

The femora of diapsids have undergone morphological changes related to shifts in postural and locomotor modes, such as the transition from plesiomorphic amniote and diapsid taxa to the apomorphic conditions related to a more erect posture within Archosauriformes. One remarkable clade of Triassic diapsids is the chameleon-like Drepanosauromorpha. This group is known from numerous articulated but heavily compressed skeletons that have the potential to further inform early reptile femoral evolution. For the first time, we describe the three-dimensional osteology of the femora of Drepanosauromorpha, based on undistorted fossils from the Upper Triassic Chinle Formation and Dockum Group of North America. We identify apomorphies and a combination of character states that link these femora to those in crushed specimens of drepanosauromorphs and compare our sample with a range of amniote taxa. Several characteristics of drepanosauromorph femora, including a hemispherical proximal articular surface, prominent asymmetry in the proximodistal length of the tibial condyles, and a deep intercondylar sulcus, are plesiomorphies shared with early diapsids. The femora contrast with those of most diapsids in lacking a crest-like, distally tapering internal trochanter. They bear a ventrolaterally positioned tuberosity on the femoral shaft, resembling the fourth trochanter in Archosauriformes. The reduction of an internal trochanter parallels independent reductions in therapsids and archosauriforms. The presence of a ventrolaterally positioned trochanter is also similar to that of chameleonid squamates. Collectively, these features demonstrate a unique femoral morphology for drepanosauromorphs, and suggest an increased capacity for femoral adduction and protraction relative to most other Permo-Triassic diapsids.

Synergistic Targeting of DNA-PK and KIT Signaling Pathways in KIT Mutant Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is the most common and aggressive form of acute leukemia, with a 5-year survival rate of just 24%. Over a third of all AML patients harbor activating mutations in kinases, such as the receptor tyrosine kinases FLT3 (receptor-type tyrosine-protein kinase FLT3) and KIT (mast/stem cell growth factor receptor kit). FLT3 and KIT mutations are associated with poor clinical outcomes and lower remission rates in response to standard-of-care chemotherapy. We have recently identified that the core kinase of the non-homologous end joining DNA repair pathway, DNA-PK (DNA-dependent protein kinase), is activated downstream of FLT3; and targeting DNA-PK sensitized FLT3-mutant AML cells to standard-of-care therapies. Herein, we investigated DNA-PK as a possible therapeutic vulnerability in KIT mutant AML, using isogenic FDC-P1 mouse myeloid progenitor cell lines transduced with oncogenic mutant KIT (V560G and D816V) or vector control. Targeted quantitative phosphoproteomic profiling identified phosphorylation of DNA-PK in the T2599/T2605/S2608/S2610 cluster in KIT mutant cells, indicative of DNA-PK activation. Accordingly, proliferation assays revealed that KIT mutant FDC-P1 cells were more sensitive to the DNA-PK inhibitors M3814 or NU7441, compared with empty vector controls. DNA-PK inhibition combined with inhibition of KIT signaling using the kinase inhibitors dasatinib or ibrutinib, or the protein phosphatase 2A activators FTY720 or AAL(S), led to synergistic cell death. Global phosphoproteomic analysis of KIT-D816V cells revealed that dasatinib and M3814 single-agent treatments inhibited extracellular signal-regulated kinase and AKT (RAC-alpha serine/threonine-protein kinase)/MTOR (serine/threonine-protein kinase mTOR) activity, with greater inhibition of both pathways when used in combination. Combined dasatinib and M3814 treatment also synergistically inhibited phosphorylation of the transcriptional regulators MYC and MYB. This study provides insight into the oncogenic pathways regulated by DNA-PK beyond its canonical role in DNA repair and demonstrates that DNA-PK is a promising therapeutic target for KIT mutant cancers.

Blood flow restriction during self-paced aerobic intervals reduces mechanical and cardiovascular demands without modifying neuromuscular fatigue.

This study examined cardiovascular, perceptual and neuromuscular fatigue characteristics during and after cycling intervals with and without blood flow restriction (BFR). Fourteen endurance cyclists/triathletes completed four 4-minute self-paced aerobic cycling intervals at the highest sustainable intensity, with and without intermittent BFR (60% of arterial occlusion pressure). Rest interval durations were six, four and four minutes, respectively. Power output, cardiovascular demands and ratings of perceived exertion (RPE) were averaged over each interval. Knee extension torque and vastus lateralis electromyography responses following electrical stimulation of the femoral nerve were recorded pre-exercise, post-interval one (+1, 2 and 4-minutes) and post-interval four (+1, 2, 4, 6 and 8-minutes). Power output during BFR intervals was lower than non-BFR (233 ± 54 vs 282 ± 60 W, p < 0.001). Oxygen uptake and heart rate during BFR intervals were lower compared to non-BFR (38.7 ± 4.5 vs 44.7 ± 6.44 mL kg-1 min-1, p < 0.001; 160 ± 14 vs 166 ± 10 bpm, p < 0.001), while RPE was not different between conditions. Compared to pre-exercise, maximal voluntary contraction torque and peak twitch torque were reduced after the first interval with further reductions following the fourth interval (p < 0.001) independent of condition (p = 0.992). Voluntary activation (twitch interpolation) did not change between timepoints (p = 0.375). Overall, intermittent BFR reduced the mechanical and cardiovascular demands of self-paced intervals without modifying RPE or knee-extensor neuromuscular characteristics. Therefore, BFR reduced the cardiovascular demands while maintaining the muscular demands associated with self-paced intervals. Self-paced BFR intervals could be used to prevent cardiovascular and perceptual demands being the limiting factor of exercise intensity, thus allowing greater physiological muscular demands compared to intervals without BFR.HighlightsThe use of blood flow restriction (BFR) during self-paced intervals (at the highest perceived sustainable intensity) causes a reduction in power output, pulmonary oxygen uptake and heart rate compared with non-restricted self-paced intervals.Despite lower mechanical and physiological demands during BFR cycling, the magnitude and aetiology of neuromuscular fatigue were not different to intervals without BFR, indicating the internal muscular load during BFR was elevated and potentially equivalent compared to without BFR.Self-paced intervals could be a suitable model to prescribe aerobic BFR exercise as an adjunct training stimulus for endurance cyclists.

Phospho-heavy-labeled-spiketide FAIMS stepped-CV DDA (pHASED) provides real-time phosphoproteomics data to aid in cancer drug selection.

Global high-throughput phosphoproteomic profiling is increasingly being applied to cancer specimens to identify the oncogenic signaling cascades responsible for promoting disease initiation and disease progression; pathways that are often invisible to genomics analysis. Hence, phosphoproteomic profiling has enormous potential to inform and improve individualized anti-cancer treatment strategies. However, to achieve the adequate phosphoproteomic depth and coverage necessary to identify the activated, and hence, targetable kinases responsible for driving oncogenic signaling pathways, affinity phosphopeptide enrichment techniques are required and often coupled with offline high-pressure liquid chromatographic (HPLC) separation prior to nanoflow liquid chromatography-tandem mass spectrometry (nLC-MS/MS). These complex and time-consuming procedures, limit the utility of phosphoproteomics for the analysis of individual cancer patient specimens in real-time, and restrict phosphoproteomics to specialized laboratories often outside of the clinical setting. To address these limitations, here we have optimized a new protocol, phospho-heavy-labeled-spiketide FAIMS Stepped-CV DDA (pHASED), that employs online phosphoproteome deconvolution using high-field asymmetric waveform ion mobility spectrometry (FAIMS) and internal phosphopeptide standards to provide accurate label-free quantitation (LFQ) data in real-time. Compared with traditional single-shot LFQ phosphoproteomics workflows, pHASED provided increased phosphoproteomic depth and coverage (phosphopeptides = 4617 pHASED, 2789 LFQ), whilst eliminating the variability associated with offline prefractionation. pHASED was optimized using tyrosine kinase inhibitor (sorafenib) resistant isogenic FLT3-mutant acute myeloid leukemia (AML) cell line models. Bioinformatic analysis identified differential activation of the serine/threonine protein kinase ataxia-telangiectasia mutated (ATM) pathway, responsible for sensing and repairing DNA damage in sorafenib-resistant AML cell line models, thereby uncovering a potential therapeutic opportunity. Herein, we have optimized a rapid, reproducible, and flexible protocol for the characterization of complex cancer phosphoproteomes in real-time, a step towards the implementation of phosphoproteomics in the clinic to aid in the selection of anti-cancer therapies for patients.

Telehealth treatment for gambling disorder in the COVID-19 era: seismic shifts and silver linings.

PURPOSE OF REVIEW: Gambling disorder is a serious mental health condition and the only behavioral addiction currently recognized by the American Psychiatric Association. Though prevalence and treatment seeking for gambling disorder have been stable for decades, the global COVID-19 pandemic has created a seismic shift in societal factors that influence gambling disorder and treatment availability. At the same time, the increasing availability of telehealth therapy for gambling disorder offers a new way to provide specialized treatment nationwide. RECENT FINDINGS: The present review discusses the seismic shifts in underlying risk factors, gambling availability, and reduced access to treatment. It also covers the emergence of telehealth treatment for gambling disorder, including its benefits and pitfalls. SUMMARY: In separate commentaries, several experts hypothesized that the pandemic was likely to increase mental health risk factors in society such as social isolation, job loss, and stress. In addition, access to online gambling also increased, while countries that locked down more strictly (like Singapore) saw a reduction in terrestrial gambling, countries that did not lock down strictly (like Sweden) did not see changes in gambling behavior. Telehealth was almost universally recommended as a good option for treatment in the studies we reviewed, though proper training and staffing are needed for telehealth to prove effective. Gambling disorder was only included in nationwide addiction telehealth programs in two countries.

Self-Paced Cycling at the Highest Sustainable Intensity With Blood Flow Restriction Reduces External but Not Internal Training Loads.

PURPOSE: This study compared training loads and internal:external load ratios from an aerobic interval session at the highest perceptually sustainable intensity with and without blood flow restriction (BFR). METHODS: On separate days, 14 endurance cyclists/triathletes completed four 4-minute self-paced aerobic cycling intervals at their highest sustainable intensity, with and without BFR (60% of arterial occlusion pressure). Internal training load was quantified using 3 training impulses (TRIMP; Banister, Lucia, and Edwards) and sessional ratings of perceived exertion. External load was assessed using total work done (TWD). Training load ratios between all internal loads were calculated relative to TWD. RESULTS: Lucia TRIMP was lower for the BFR compared with non-BFR session (49 [9] vs 53 [8] arbitrary units [au], P = .020, dz = -0.71). No between-conditions differences were observed for Banister TRIMP (P = .068), Edwards TRIMP (P = .072), and training load in sessional ratings of perceived exertion (P = .134). The TWD was lower for the BFR compared with non-BFR session (223 [52] vs 271 [58] kJ, P < .001, dz = -1.27). Ratios were greater for the BFR session compared with non-BFR for Lucia TRIMP:TWD (0.229 [0.056] vs 0.206 [0.056] au, P < .001, dz = 1.21), Edwards TRIMP:TWD (0.396 [0.105] vs 0.370 [0.088] au, P = .031, dz = 0.66), and training load in sessional ratings of perceived exertion:TWD (1.000 [0.266] vs 0.890 [0.275] au, P = .044, dz = 0.60), but not Banister TRIMP:TWD (P = .306). CONCLUSIONS: Practitioners should consider both internal and external loads when monitoring BFR exercise to ensure the demands are appropriately captured. These BFR-induced changes were reflected by the Lucia TRIMP:TWD and Edwards TRIMP:TWD ratio, which could be used to monitor aerobic BFR training loads. The Lucia TRIMP:TWD ratio likely represents BFR-induced changes more appropriately compared with ratios involving either Edwards or Banister TRIMP.

New giant carnivorous dinosaur reveals convergent evolutionary trends in theropod arm reduction.

Giant carnivorous dinosaurs such as Tyrannosaurus rex and abelisaurids are characterized by highly reduced forelimbs that stand in contrast to their huge dimensions, massive skulls, and obligate bipedalism.1,2 Another group that follows this pattern, yet is still poorly known, is the Carcharodontosauridae: dominant predators that inhabited most continents during the Early Cretaceous3-5 and reached their largest sizes in Aptian-Cenomanian times.6-10 Despite many discoveries over the last three decades, aspects of their anatomy, especially with regard to the skull, forearm, and feet, remain poorly known. Here we report a new carcharodontosaurid, Meraxes gigas, gen. et sp. nov., based on a specimen recovered from the Upper Cretaceous Huincul Formation of northern Patagonia, Argentina. Phylogenetic analysis places Meraxes among derived Carcharodontosauridae, in a clade with other massive South American species. Meraxes preserves novel anatomical information for derived carcharodontosaurids, including an almost complete forelimb that provides evidence for convergent allometric trends in forelimb reduction among three lineages of large-bodied, megapredatory non-avian theropods, including a remarkable degree of parallelism between the latest-diverging tyrannosaurids and carcharodontosaurids. This trend, coupled with a likely lower bound on forelimb reduction, hypothesized to be about 0.4 forelimb/femur length, combined to produce this short-armed pattern in theropods. The almost complete cranium of Meraxes permits new estimates of skull length in Giganotosaurus, which is among the longest for theropods. Meraxes also provides further evidence that carchardontosaurids reached peak diversity shortly before their extinction with high rates of trait evolution in facial ornamentation possibly linked to a social signaling role.

Aerobic Training With Blood Flow Restriction for Endurance Athletes: Potential Benefits and Considerations of Implementation.

ABSTRACT: Smith, NDW, Scott, BR, Girard, O, and Peiffer, JJ. Aerobic training with blood flow restriction for endurance athletes: potential benefits and considerations of implementation. J Strength Cond Res 36(12): 3541-3550, 2022-Low-intensity aerobic training with blood flow restriction (BFR) can improve maximal oxygen uptake, delay the onset of blood lactate accumulation, and may provide marginal benefits to economy of motion in untrained individuals. Such a training modality could also improve these physiological attributes in well-trained athletes. Indeed, aerobic BFR training could be beneficial for those recovering from injury, those who have limited time for training a specific physiological capacity, or as an adjunct training stimulus to provide variation in a program. However, similarly to endurance training without BFR, using aerobic BFR training to elicit physiological adaptations in endurance athletes will require additional considerations compared with nonendurance athletes. The objective of this narrative review is to discuss the acute and chronic aspects of aerobic BFR exercise for well-trained endurance athletes and highlight considerations for its effective implementation. This review first highlights key physiological capacities of endurance performance. The acute and chronic responses to aerobic BFR exercise and their impact on performance are then discussed. Finally, considerations for prescribing and monitoring aerobic BFR exercise in trained endurance populations are addressed to challenge current views on how BFR exercise is implemented.

Exceptionally simple, rapidly replaced teeth in sauropod dinosaurs demonstrate a novel evolutionary strategy for herbivory in Late Jurassic ecosystems.

BACKGROUND: Dinosaurs dominated terrestrial environments for over 100 million years due in part to innovative feeding strategies. Although a range of dental adaptations was present in Late Jurassic dinosaurs, it is unclear whether dinosaur ecosystems exhibited patterns of tooth disparity and dietary correlation similar to those of modern amniotes, in which carnivores possess simple teeth and herbivores exhibit complex dentitions. To investigate these patterns, we quantified dental shape in Late Jurassic dinosaurs to test relationships between diet and dental complexity. RESULTS: Here, we show that Late Jurassic dinosaurs exhibited a disparity of dental complexities on par with those of modern saurians. Theropods possess relatively simple teeth, in spite of the range of morphologies tested, and is consistent with their inferred carnivorous habits. Ornithischians, in contrast, have complex dentitions, corresponding to herbivorous habits. The dentitions of macronarian sauropods are similar to some ornithischians and living herbivorous squamates but slightly more complex than other sauropods. In particular, all diplodocoid sauropods investigated possess remarkably simple teeth. The existence of simple teeth in diplodocoids, however, contrasts with the pattern observed in nearly all known herbivores (living or extinct). CONCLUSIONS: Sauropod dinosaurs exhibit a novel approach to herbivory not yet observed in other amniotes. We demonstrate that sauropod tooth complexity is related to tooth replacement rate rather than diet, which contrasts with the results from mammals and saurians. This relationship is unique to the sauropod clade, with ornithischians and theropods displaying the patterns observed in other groups. The decoupling of herbivory and tooth complexity paired with a correlation between complexity and replacement rate demonstrates a novel evolutionary strategy for plant consumption in sauropod dinosaurs.

Influence of angular position on radar gun peak cricket ball speed measurements.

The purpose of this study was to determine the agreement in peak ball speed measured using a radar gun and motion capture system then examine the influence of angular position. Peak ball speed was recorded with the radar gun in-line with the ball trajectory (0° offset) and at 5° offsets up to 35°. Agreement between devices was calculated at 0° and for grouped offset bins (0-5°, 10-15°, 20-25°, and 30-35°). At 0°, a strong correlation (r = 0.99) and intraclass correlation coefficient (.984) were observed with a systematic overestimation by the radar gun (1.7 ± 0.8 m/s). The residual speed between devices at the 30-35° offset was significantly different to both 0-5° (p < .001) and 10-15° (p < .001) offsets. The radar gun consistently overestimated peak ball speed up to a ~20° offset and thus can be positioned out of the line-of-throw to avoid obstructions.

Preclinical and clinical evaluation of German-sourced ONC201 for the treatment of H3K27M-mutant diffuse intrinsic pontine glioma.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brainstem tumor for which radiation is the only treatment. Case studies report a clinical response to ONC201 for patients with H3K27M-mutant gliomas. Oncoceutics (ONC201) is only available in the United States and Japan; however, in Germany, DIPG patients can be prescribed and dispensed a locally produced compound-ONC201 German-sourced ONC201 (GsONC201). Pediatric oncologists face the dilemma of supporting the administration of GsONC201 as conjecture surrounds its authenticity. Therefore, we compared GsONC201 to original ONC201 manufactured by Oncoceutics Inc. METHODS: Authenticity of GsONC201 was determined by high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Biological activity was shown via assessment of on-target effects, in vitro growth, proliferation, and apoptosis analysis. Patient-derived xenograft mouse models were used to assess plasma and brain tissue pharmacokinetics, pharmacodynamics, and overall survival (OS). The clinical experience of 28 H3K27M+ mutant DIPG patients who received GsONC201 (2017-2020) was analyzed. RESULTS: GsONC201 harbored the authentic structure, however, was formulated as a free base rather than the dihydrochloride salt used in clinical trials. GsONC201 in vitro and in vivo efficacy and drug bioavailability studies showed no difference compared to Oncoceutics ONC201. Patients treated with GsONC201 (n = 28) showed a median OS of 18 months (P = .0007). GsONC201 patients who underwent reirradiation showed a median OS of 22 months compared to 12 months for GsONC201 patients who did not (P = .012). CONCLUSIONS: This study confirms the biological activity of GsONC201 and documents the OS of patients who received the drug; however, GsONC201 was never used as a monotherapy.

Enigmatic dinosaur precursors bridge the gap to the origin of Pterosauria.

Pterosaurs were the first vertebrates to evolve powered flight1 and comprised one of the main evolutionary radiations in terrestrial ecosystems of the Mesozoic era (approximately 252-66 million years ago), but their origin has remained an unresolved enigma in palaeontology since the nineteenth century2-4. These flying reptiles have been hypothesized to be the close relatives of a wide variety of reptilian clades, including dinosaur relatives2-8, and there is still a major morphological gap between those forms and the oldest, unambiguous pterosaurs from the Upper Triassic series. Here, using recent discoveries of well-preserved cranial remains, microcomputed tomography scans of fragile skull bones (jaws, skull roofs and braincases) and reliably associated postcrania, we demonstrate that lagerpetids-a group of cursorial, non-volant dinosaur precursors-are the sister group of pterosaurs, sharing numerous synapomorphies across the entire skeleton. This finding substantially shortens the temporal and morphological gap between the oldest pterosaurs and their closest relatives and simultaneously strengthens the evidence that pterosaurs belong to the avian line of archosaurs. Neuroanatomical features related to the enhanced sensory abilities of pterosaurs9 are already present in lagerpetids, which indicates that these features evolved before flight. Our evidence illuminates the first steps of the assembly of the pterosaur body plan, whose conquest of aerial space represents a remarkable morphofunctional innovation in vertebrate evolution.

Osteohistological analyses reveal diverse strategies of theropod dinosaur body-size evolution.

The independent evolution of gigantism among dinosaurs has been a topic of long-standing interest, but it remains unclear if gigantic theropods, the largest bipeds in the fossil record, all achieved massive sizes in the same manner, or through different strategies. We perform multi-element histological analyses on a phylogenetically broad dataset sampled from eight theropod families, with a focus on gigantic tyrannosaurids and carcharodontosaurids, to reconstruct the growth strategies of these lineages and test if particular bones consistently preserve the most complete growth record. We find that in skeletally mature gigantic theropods, weight-bearing bones consistently preserve extensive growth records, whereas non-weight-bearing bones are remodelled and less useful for growth reconstruction, contrary to the pattern observed in smaller theropods and some other dinosaur clades. We find a heterochronic pattern of growth fitting an acceleration model in tyrannosaurids, with allosauroid carcharodontosaurids better fitting a model of hypermorphosis. These divergent growth patterns appear phylogenetically constrained, representing extreme versions of the growth patterns present in smaller coelurosaurs and allosauroids, respectively. This provides the first evidence of a lack of strong mechanistic or physiological constraints on size evolution in the largest bipeds in the fossil record and evidence of one of the longest-living individual dinosaurs ever documented.