EGFRvIII Confers Sensitivity to Saracatinib in a STAT5-Dependent Manner in Glioblastoma.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with few effective treatments. EGFR alterations, including expression of the truncated variant EGFRvIII, are among the most frequent genomic changes in these tumors. EGFRvIII is known to preferentially signal through STAT5 for oncogenic activation in GBM, yet targeting EGFRvIII has yielded limited clinical success to date. In this study, we employed patient-derived xenograft (PDX) models expressing EGFRvIII to determine the key points of therapeutic vulnerability within the EGFRvIII-STAT5 signaling axis in GBM. Our findings reveal that exogenous expression of paralogs STAT5A and STAT5B augments cell proliferation and that inhibition of STAT5 phosphorylation in vivo improves overall survival in combination with temozolomide (TMZ). STAT5 phosphorylation is independent of JAK1 and JAK2 signaling, instead requiring Src family kinase (SFK) activity. Saracatinib, an SFK inhibitor, attenuates phosphorylation of STAT5 and preferentially sensitizes EGFRvIII+ GBM cells to undergo apoptotic cell death relative to wild-type EGFR. Constitutively active STAT5A or STAT5B mitigates saracatinib sensitivity in EGFRvIII+ cells. In vivo, saracatinib treatment decreased survival in mice bearing EGFR WT tumors compared to the control, yet in EGFRvIII+ tumors, treatment with saracatinib in combination with TMZ preferentially improves survival.

Discrete-state models identify pathway specific B cell states across diseases and infections at single-cell resolution.

Oxygen (O2) regulated pathways modulate B cell activation, migration and proliferation during infection, vaccination, and other diseases. Modeling these pathways in health and disease is critical to understand B cell states and ways to mediate them. To characterize B cells by their activation of O2 regulated pathways we develop pathway specific discrete state models using previously published single-cell RNA-sequencing (scRNA-seq) datasets from isolated B cells. Specifically, Single Cell Boolean Omics Network Invariant-Time Analysis (scBONITA) was used to infer logic gates for known pathway topologies. The simplest inferred set of logic gates that maximized the number of "OR" interactions between genes was used to simulate B cell networks involved in oxygen sensing until they reached steady network states (attractors). By focusing on the attractors that best represented sequenced cells, we identified genes critical in determining pathway specific cellular states that corresponded to diseased and healthy B cell phenotypes. Specifically, we investigate the transendothelial migration, regulation of actin cytoskeleton, HIF1A, and Citrate Cycle pathways. Our analysis revealed attractors that resembled the state of B cell exhaustion in HIV+ patients as well as attractors that promoted anerobic metabolism, angiogenesis, and tumorigenesis in breast cancer patients, which were eliminated after neoadjuvant chemotherapy (NACT). Finally, we investigated the attractors to which the Azimuth-annotated B cells mapped and found that attractors resembling B cells from HIV+ patients encompassed a significantly larger number of atypical memory B cells than HIV- attractors. Meanwhile, attractors resembling B cells from breast cancer patients post NACT encompassed a reduced number of atypical memory B cells compared to pre-NACT attractors.

Stable isotopes show Homo sapiens dispersed into cold steppes ~45,000 years ago at Ilsenhöhle in Ranis, Germany.

The spread of Homo sapiens into new habitats across Eurasia ~45,000 years ago and the concurrent disappearance of Neanderthals represents a critical evolutionary turnover in our species' history. 'Transitional' technocomplexes, such as the Lincombian-Ranisian-Jerzmanowician (LRJ), characterize the European record during this period but their makers and evolutionary significance have long remained unclear. New evidence from Ilsenhöhle in Ranis, Germany, now provides a secure connection of the LRJ to H. sapiens remains dated to ~45,000 years ago, making it one of the earliest forays of our species to central Europe. Using many stable isotope records of climate produced from 16 serially sampled equid teeth spanning ~12,500 years of LRJ and Upper Palaeolithic human occupation at Ranis, we review the ability of early humans to adapt to different climate and habitat conditions. Results show that cold climates prevailed across LRJ occupations, with a temperature decrease culminating in a pronounced cold excursion at ~45,000-43,000 cal BP. Directly dated H. sapiens remains confirm that humans used the site even during this very cold phase. Together with recent evidence from the Initial Upper Palaeolithic, this demonstrates that humans operated in severe cold conditions during many distinct early dispersals into Europe and suggests pronounced adaptability.

The ecology, subsistence and diet of ~45,000-year-old Homo sapiens at Ilsenhöhle in Ranis, Germany.

Recent excavations at Ranis (Germany) identified an early dispersal of Homo sapiens into the higher latitudes of Europe by 45,000 years ago. Here we integrate results from zooarchaeology, palaeoproteomics, sediment DNA and stable isotopes to characterize the ecology, subsistence and diet of these early H. sapiens. We assessed all bone remains (n = 1,754) from the 2016-2022 excavations through morphology (n = 1,218) or palaeoproteomics (zooarchaeology by mass spectrometry (n = 536) and species by proteome investigation (n = 212)). Dominant taxa include reindeer, cave bear, woolly rhinoceros and horse, indicating cold climatic conditions. Numerous carnivore modifications, alongside sparse cut-marked and burnt bones, illustrate a predominant use of the site by hibernating cave bears and denning hyaenas, coupled with a fluctuating human presence. Faunal diversity and high carnivore input were further supported by ancient mammalian DNA recovered from 26 sediment samples. Bulk collagen carbon and nitrogen stable isotope data from 52 animal and 10 human remains confirm a cold steppe/tundra setting and indicate a homogenous human diet based on large terrestrial mammals. This lower-density archaeological signature matches other Lincombian-Ranisian-Jerzmanowician sites and is best explained by expedient visits of short duration by small, mobile groups of pioneer H. sapiens.

Homo sapiens reached the higher latitudes of Europe by 45,000 years ago.

The Middle to Upper Palaeolithic transition in Europe is associated with the regional disappearance of Neanderthals and the spread of Homo sapiens. Late Neanderthals persisted in western Europe several millennia after the occurrence of H. sapiens in eastern Europe1. Local hybridization between the two groups occurred2, but not on all occasions3. Archaeological evidence also indicates the presence of several technocomplexes during this transition, complicating our understanding and the association of behavioural adaptations with specific hominin groups4. One such technocomplex for which the makers are unknown is the Lincombian-Ranisian-Jerzmanowician (LRJ), which has been described in northwestern and central Europe5-8. Here we present the morphological and proteomic taxonomic identification, mitochondrial DNA analysis and direct radiocarbon dating of human remains directly associated with an LRJ assemblage at the site Ilsenhöhle in Ranis (Germany). These human remains are among the earliest directly dated Upper Palaeolithic H. sapiens remains in Eurasia. We show that early H. sapiens associated with the LRJ were present in central and northwestern Europe long before the extinction of late Neanderthals in southwestern Europe. Our results strengthen the notion of a patchwork of distinct human populations and technocomplexes present in Europe during this transitional period.

Associations between 24-h movement guidelines compliance and anxiety and depression among youth receiving special education services in the US.

BACKGROUND: Youth with disabilities are five times more likely to experience anxiety or depression than peers without disabilities. Engagement in sufficient daily physical activity (PA), adequate nightly sleep, and limited daily screen time (collectively known as 24-h movement guidelines) is associated with lower odds of anxiety and depression for peers without disabilities. Extending the investigation of these modifiable behaviors to youth with disabilities is warranted. OBJECTIVE: To estimate the association between meeting 24-h movement guidelines and anxiety and depression among a nationally representative sample of youth with disabilities. METHODS: A cross-sectional secondary analysis of the 2019-2020 NSCH was conducted and included youth 6-17 years old who were currently receiving special education services. Weighted prevalence estimates and logistic regressions were employed to estimate the association between meeting guidelines (separately and combined) and current anxiety or depression status. RESULTS: Compared to youth with disabilities who met the guideline, those not meeting the sleep or screen time guidelines, independently, had significantly higher odds of depression, or anxiety (aOR range 1.53, 2.31 respectively). Comparable odds were observed between those meeting the PA guidelines, alone or in combination, and those meeting none of the 24-h movement guidelines. CONCLUSION: Adequate nightly sleep, and limited screen time, were significantly associated with anxiety and depression among youth with disabilities, a pattern consistent to peers without disabilities. Yet, meeting more than one guideline did not further reduce odds of poor mental health, warranting further investigation of compounding benefits of the 24-h guidelines within this population.

Mindfulness and loneliness in retired older adults in China: mediation effects of positive and negative affect.

Objectives: Drawing from the mindfulness framework and the broaden-and-build theory, this study investigates the extent to which mindfulness influences loneliness and whether the relation is mediated by positive and negative affect.Method: Data were collected from 748 retired older adults aged 60 and above in Chengdu, China in 2022. Loneliness and mindfulness were measured by the UCLA loneliness scale and by the short-form version of the Five Facet Mindfulness Questionnaire, while the positive and negative affect was assessed by the International Positive and Negative Affect Schedule.Results: The results of this study show that mindfulness was positively associated with positive affect (ß = 0.37, p<.001), negatively related to negative affect (ß=-0.21, p<.001) and loneliness (ß=-0.13, p<.001), and had an indirect effect on loneliness via positive and negative affect (ß=-0.20, p<.001).Conclusion: The findings suggest that mindfulness could be a positive resource for improving mental health and reducing loneliness among retired older adults in China.

Racial Discrimination and Interpersonal Violence in Asian American Adolescents During the COVID-19 Pandemic.

PURPOSE: Racial discrimination targeting Asians in the United States has increased sharply since the COVID-19 pandemic. Despite a well-established link with mental/physical health outcomes, little is known about how racial discrimination relates to interpersonal violence, particularly in adolescents. To address this gap in knowledge, we examined cross-sectional and longitudinal (1-year follow-up) associations between racial discrimination and interpersonal violence perpetration and victimization in Asian American adolescents in a large US city. METHODS: Data from Waves 3 (2020) and 4 (2021) of a randomized clinical trial of a school-based violence prevention program were examined. We limited our sample to participants who identified as Asian American (n = 344; 48.3% female; Meanage = 14.6 years at Wave 3). RESULTS: At Wave 3, 26.5% of the adolescents reported experiencing some form of racial discrimination, including 18.3% experiencing verbal harassment due to race and 16.0% reporting inequitable treatment due to race. Relative to their nonvictimized counterparts, adolescents who experienced racial discrimination were more likely to report being a victim of bullying and teen dating violence cross-sectionally and being a bullying victim longitudinally. Moreover, those who experienced racial discrimination reported more bullying and teen dating violence perpetration concurrently, as well as more dating violence perpetration 1 year later. DISCUSSION: In the understudied population of Asian American adolescents, we found that experiencing racial discrimination contributes to both interpersonal violence victimization and perpetration. Youth violence prevention could include strategies addressing racial discrimination.

CT findings in idiopathic myointimal hyperplasia of mesenteric veins (IMHMV) and comparison to other colitides.

PURPOSE: The purpose of this study is to determine computed tomography (CT) findings that aid in differentiating idiopathic myointimal hyperplasia of mesenteric veins (IMHMV) from other colitides. METHODS: Retrospective review of histiologic proven cases of IMHMV (n = 12) with contrast enhanced CT (n = 11) and/or computed tomography angiography (CTA) (n = 9) exams. Control groups comprised of CT of infectious colitis (n = 13), CT of inflammatory bowel disease (IBD) (n = 12), and CTA of other colitides (n = 13). CT exams reviewed by 2 blinded gastrointestinal radiologists for maximum bowel wall thickness, enhancement pattern, decreased bowel wall enhancement, submucosal attenuation value, presence and location of IMV occlusion, peripheral mesenteric venous occlusion, dilated pericolonic veins, subjective IMA dilation, maximum IMA diameter, maximum peripheral IMA branch diameter, ascites, and mesenteric edema. Presence of early filling veins was an additional finding evaluated on CTA exams. RESULTS: Statistically significant CT findings of IMHMV compared to control groups included greater maximum bowel wall thickness, decreased bowel enhancement, IMV occlusion, and peripheral mesenteric venous occlusion (p < 0.05). Dilated pericolonic veins were seen more frequently in IMHMV compared to the infectious colitis group (64% versus 15%, p = 0.02). Additional statistically significant finding on CTA included early filling veins in IMHMV compared to the CTA control group (100% versus 46%, p = 0.008). CONCLUSION: IMHMV is a rare chronic non-thrombotic ischemia predominantly involving the rectosigmoid colon. CT features that may aid in differentiating IMHMV from other causes of left-sided colitis include marked bowel wall thickening with decreased enhancement, IMV and peripheral mesenteric venous occlusion or tapering, and early filling of dilated veins on CTA.

Building an Understanding of Proteostasis in Reproductive Cells: The Impact of Reactive Carbonyl Species on Protein Fate.

Significance: Stringent regulation of protein homeostasis pathways, under both physiological and pathological conditions, is necessary for the maintenance of proteome fidelity and optimal cell functioning. However, when challenged by endogenous or exogenous stressors, these proteostasis pathways can become dysregulated with detrimental consequences for protein fate, cell survival, and overall organism health. Most notably, there are numerous somatic pathologies associated with a loss of proteostatic regulation, including neurodegenerative disorders, type 2 diabetes, and some cancers. Recent Advances: Lipid oxidation-derived reactive carbonyl species (RCS), such as 4-hydroxynonenal (4HNE) and malondialdehyde, are relatively underappreciated purveyors of proteostatic dysregulation, which elicit their effects via the nonenzymatic post-translational modification of proteins. Emerging evidence suggests that a subset of germline proteins can serve as substrates for 4HNE modification. Among these, prevalent targets include succinate dehydrogenase, heat shock protein A2 and A-kinase anchor protein 4, all of which are intrinsically associated with fertility. Critical Issues: Despite growing knowledge in this field, the RCS adductomes of spermatozoa and oocytes are yet to be comprehensively investigated. Furthermore, the manner by which RCS-mediated adduction impacts protein fate and drives cellular responses, such as protein aggregation, requires further examination in the germline. Given that RCS-protein adduction has been attributed a role in infertility, there has been sparked research investment into strategies to prevent lipid peroxidation in germ cells. Future Directions: An increased depth of knowledge regarding the mechanisms and substrates of RCS-mediated protein modification in reproductive cells may reveal important targets for the development of novel therapies to improve fertility and pregnancy outcomes for future generations.

More frequent naps are associated with lower cognitive development in a cohort of 8-38-month-old children, during the Covid-19 pandemic.

Background: How often a child naps, during infancy, is believed to reflect both intrinsic factors, that is, the need of an immature brain to consolidate information soon after it is acquired, and environmental factors. Difficulty accounting for important environmental factors that interfere with a child's sleep needs (e.g., attending daycare) has clouded our ability to understand the role of intrinsic drivers of napping frequency. Methods: Here we investigate sleep patterns in association with two measures of cognitive ability, vocabulary size, measured with the Oxford-Communicative Development Inventory (N = 298) and cognitive executive functions (EF), measured with the Early EF Questionnaire (N = 463), in a cohort of 8-38-month-olds. Importantly, because of the social distancing measures imposed during the Covid-19 Spring 2020 lockdown, in the UK, measures of sleep were taken when children did not access daycare settings. Results: We find that children with more frequent but shorter naps than expected for their age had lower concurrent receptive vocabularies, lower cognitive EF and a slower increase in expressive vocabulary from spring to winter 2020, when age, sex, and SES were accounted for. The negative association between vocabulary and frequency of naps became stronger with age. Conclusions: These findings suggest that the structure of daytime sleep is an indicator of cognitive development and highlight the importance of considering environmental perturbations and age when investigating developmental correlates of sleep.

Measuring Health Professionals' Skills and Self-Efficacy for Communicating with Individuals with Disabilities: Instrument Development and Validation.

Individuals with disabilities experience numerous health disparities compared to their non-disabled peers and face inequities associated with challenges accessing care, stigma, and bias. Health professionals have the opportunity to address health inequities through improved communication, a primary barrier to receiving quality care; however more training is needed. There are limitations to existing tools to measure the skills or self-efficacy of professionals to communicate with individuals with disabilities, and to assess the effectiveness of training programs. The purpose of this study was to develop and validate an instrument to measure health professionals' communication skills and self-efficacy specifically related to working with individuals with disabilities. After a comprehensive review of literature, expert review of proposed scale items, and pilot test, a 19-item survey was administered to 237 healthcare and health and physical education professionals. Construct validity was evaluated by performing an exploratory factor analysis on each subscale and Cronbach's alpha coefficient was used to measure internal consistency. For the skills subscale, Cronbach's α = .919 and for the self-efficacy subscale Cronbach's α = .949 after the removal of one item, resulting in a final 18-item inventory that demonstrates strong validity and reliability.

E-prescribing and medication safety in community settings: A rapid scoping review.

Background: Medication prescribing is essential for the treatment, curing, maintenance, and/or prevention of an illness and disease, however, medication errors remain common. Common errors including prescribing and administration, pose significant risk to patients. Electronic prescribing (e-prescribing) is one intervention used to enhance the safety and quality of prescribing by decreasing medication errors and reducing harm. E-prescribing in community-based settings has not been extensively examined. Objective: To map and characterize the current evidence on e-prescribing and medication safety in community pharmacy settings. Methods: We conducted a rapid scoping review of quantitative, qualitative, and mixed methods studies reporting on e-prescribing and medication safety. MEDLINE All (OVID), Embase (Elsevier), CINAHL Full Text (EBSCOHost), and Scopus (Elsevier) databases were searched December 2022 using keywords and MeSH terms related to e-prescribing, medication safety, efficiency, and uptake. Articles were imported to Covidence and screened by two reviewers. Data were extracted by a single reviewer and verified by a second reviewer using a standardized data extraction form. Findings are reported in accordance with JBI Manual for Evidence Synthesis following thematic analysis to narratively describe results. Results: Thirty-five studies were included in this review. Most studies were quantitative (n = 22), non-experimental study designs (n = 16) and were conducted in the United States (n = 18). Half of included studies reported physicians as the prescriber (n = 18), while the remaining reported a mix of nurse practitioners, pharmacists, and physician assistants (n = 6). Studies reported on types of errors, including prescription errors (n = 20), medication safety errors (n = 9), dispensing errors (n = 2), and administration errors (n = 1). Few studies examined patient health outcomes, such as adverse drug events (n = 5). Conclusions: Findings indicate that most research is descriptive in nature and focused primarily on rates of prescription errors. Further research, such as experimental, implementation, and evaluation mixed-methods research, is needed to investigate the effects of e-prescribing on reducing error rates and improving patient and health system outcomes.

Comparing extraction method efficiency for high-throughput palaeoproteomic bone species identification.

High-throughput proteomic analysis of archaeological skeletal remains provides information about past fauna community compositions and species dispersals in time and space. Archaeological skeletal remains are a finite resource, however, and therefore it becomes relevant to optimize methods of skeletal proteome extraction. Ancient proteins in bone specimens can be highly degraded and consequently, extraction methods for well-preserved or modern bone might be unsuitable for the processing of highly degraded skeletal proteomes. In this study, we compared six proteomic extraction methods on Late Pleistocene remains with variable levels of proteome preservation. We tested the accuracy of species identification, protein sequence coverage, deamidation, and the number of post-translational modifications per method. We find striking differences in obtained proteome complexity and sequence coverage, highlighting that simple acid-insoluble proteome extraction methods perform better in highly degraded contexts. For well-preserved specimens, the approach using EDTA demineralization and protease-mix proteolysis yielded a higher number of identified peptides. The protocols presented here allowed protein extraction from ancient bone with a minimum number of working steps and equipment and yielded protein extracts within three working days. We expect further development along this route to benefit large-scale screening applications of relevance to archaeological and human evolution research.

Functional knockout of the TRPV1 channel has no effect on the exercise pressor reflex in rats.

The role played by the transient receptor potential vanilloid 1 (TRPV1) channel on the thin fibre afferents evoking the exercise pressor reflex is controversial. To shed light on this controversy, we compared the exercise pressor reflex between newly developed TRPV1+/+ , TRPV1+/- and TRPV1-/- rats. Carotid arterial injection of capsaicin (0.5 µg), evoked significant pressor responses in TRPV1+/+ and TRPV1+/- rats, but not in TRPV1-/- rats. In acutely isolated dorsal root ganglion neurons innervating the gastrocnemius muscles, capsaicin evoked inward currents in neurons isolated from TRPV1+/+ and TRPV1+/- rats but not in neurons isolated from TRPV1-/- rats. The reflex was evoked by stimulating the tibial nerve in decerebrated rats whose femoral artery was either freely perfused or occluded. We found no difference between the reflex in the three groups of rats regardless of the patency of the femoral artery. For example, the peak pressor responses to contraction in TRPV1+/+ , TRPV1+/- and TRPV1-/- rats with patent femoral arteries averaged 17.1 ± 7.2, 18.9 ± 12.4 and 18.4 ± 8.6 mmHg, respectively. Stimulation of the tibial nerve after paralysis with pancuronium had no effect on arterial pressure, findings which indicated that the pressor responses to contraction were not caused by electrical stimulation of afferent tibial nerve axons. We also found that expression levels of acid-sensing ion channel 1 and endoperoxide 4 receptor in the L4 and 5 dorsal root ganglia were not upregulated in the TRPV1-/- rats. We conclude that TRPV1 is not needed to evoke the exercise pressor reflex in rats whose contracting muscles have either a patent or an occluded arterial blood supply. KEY POINTS: A reflex arising in contracting skeletal muscle contributes to the increases in arterial blood pressure, cardiac output and breathing evoked by exercise. The sensory arm of the reflex comprises both mechanoreceptors and metaboreceptors, of which the latter signals that blood flow to exercising muscle is not meeting its metabolic demand. The nature of the channel on the metaboreceptor sensing a mismatch between supply and demand is controversial; some believe that it is the transient receptor potential vanilloid 1 (TRPV1) channel. Using genetically engineered rats in which the TRPV1 channel is rendered non-functional, we have shown that it is not needed to evoke the metaboreflex.

Magnetic resonance imaging characteristics of atlanto-axial subluxation in 42 dogs: Analysis of joint cavity size, subluxation distance, and craniocervical junction anomalies.

Background: Atlanto-axial (AA) subluxation can be a complex syndrome in dogs. Accurate identification and assessment of this condition are key to providing treatment and resolution. Aim: The purpose of this retrospective study was to describe the magnetic resonance imaging (MRI) characteristics of AA subluxation and associated neurologic deficits. Methods: A multicenter review of dogs with a diagnosis of AA subluxation was conducted, evaluating signalment, neurologic grade, duration of signs, and MRI characteristics. MRI characteristics included degree of spinal cord compression and joint subluxation, integrity of odontoid ligaments, presence of a dens, spinal cord signal intensity, and presence of syringohydromyelia, hydrocephalus, and Chiari-like malformation. A control population with normal AA joints was also evaluated. MR images of 42 dogs with AA subluxation were compared to 26 age and breed-matched control dogs. Results: Affected dogs had a median age of 27 months and a median weight of 2.7 kg, and the most commonly affected breed was the Yorkshire terrier (47.5%). Spinal cord signal hyperintensity, increased AA joint size, and cross-sectional cord compression at the level of the dens and mid-body C2 were associated with AA subluxation. No associations were found between cord compression, the appearance of the dens, or cord signal intensity and neurologic grade. Affected dogs did not have a higher incidence of Chiari-like malformation, syringohydromyelia, or hydrocephalus than control dogs, and their neurologic grade was not associated with MRI findings. Lack of dens and/or odontoid ligaments was associated with larger subluxations. Conclusion: Dogs with clinical signs of AA subluxation were significantly more likely to have intramedullary hyperintensity at the level of compression ( p = 0.0004), an increased AA joint cavity size ( p = 0.0005), and increased spinal cord compression at the level of dens and mid-body C2 (p ≤ 0.05). The authors suggest an AA joint cavity size >1.4 mm and a subluxation distance >2.5 mm as cutoffs for MRI diagnosis of AA subluxation in dogs. No differences were noted between dogs with AA subluxation and control dogs regarding syringohydromyelia, hydrocephalus, and Chiari-like malformation.

Did Early Pleistocene hominins control hammer strike angles when making stone tools?

In the study of Early Pleistocene stone artifacts, researchers have made considerable progress in reconstructing the technical decisions of hominins by examining various aspects of lithic technology, such as reduction sequences, hammer selection, platform preparation, core management, and raw material selection. By comparison, our understanding of the ways in which Early Pleistocene hominins controlled the delivery and application of percussive force during flaking remains limited. In this study, we focus on a key aspect of force delivery in stone knapping, namely the hammerstone striking angle (or the angle of blow), which has been shown to play a significant role in determining the knapping outcome. Using a dataset consists of 12 Early Pleistocene flake assemblages dated from 1.95 Ma to 1.4 Ma, we examined temporal patterns of the hammer striking angle by quantifying the bulb angle, a property of the flake's Hertzian cone that reflects the hammer striking angle used in flake production. We further included a Middle Paleolithic flake assemblage as a point of comparison from a later time period. In the Early Pleistocene dataset, we observed an increased association between the bulb angle and other flake variables related to flake size over time, a pattern similarly found in the Middle Paleolithic assemblage. These findings suggest that, towards the Oldowan-Acheulean transition, hominins began to systematically adjust the hammer striking angle in accordance with platform variables to detach flakes of different sizes more effectively, implying the development of a more comprehensive understanding of the role of the angle of blow in flake formation by ∼1.5 Ma.

Integrated molecular and multiparametric MRI mapping of high-grade glioma identifies regional biologic signatures.

Sampling restrictions have hindered the comprehensive study of invasive non-enhancing (NE) high-grade glioma (HGG) cell populations driving tumor progression. Here, we present an integrated multi-omic analysis of spatially matched molecular and multi-parametric magnetic resonance imaging (MRI) profiling across 313 multi-regional tumor biopsies, including 111 from the NE, across 68 HGG patients. Whole exome and RNA sequencing uncover unique genomic alterations to unresectable invasive NE tumor, including subclonal events, which inform genomic models predictive of geographic evolution. Infiltrative NE tumor is alternatively enriched with tumor cells exhibiting neuronal or glycolytic/plurimetabolic cellular states, two principal transcriptomic pathway-based glioma subtypes, which respectively demonstrate abundant private mutations or enrichment in immune cell signatures. These NE phenotypes are non-invasively identified through normalized K2 imaging signatures, which discern cell size heterogeneity on dynamic susceptibility contrast (DSC)-MRI. NE tumor populations predicted to display increased cellular proliferation by mean diffusivity (MD) MRI metrics are uniquely associated with EGFR amplification and CDKN2A homozygous deletion. The biophysical mapping of infiltrative HGG potentially enables the clinical recognition of tumor subpopulations with aggressive molecular signatures driving tumor progression, thereby informing precision medicine targeting.

Behavioral responses of terrestrial mammals to COVID-19 lockdowns.

COVID-19 lockdowns in early 2020 reduced human mobility, providing an opportunity to disentangle its effects on animals from those of landscape modifications. Using GPS data, we compared movements and road avoidance of 2300 terrestrial mammals (43 species) during the lockdowns to the same period in 2019. Individual responses were variable with no change in average movements or road avoidance behavior, likely due to variable lockdown conditions. However, under strict lockdowns 10-day 95th percentile displacements increased by 73%, suggesting increased landscape permeability. Animals' 1-hour 95th percentile displacements declined by 12% and animals were 36% closer to roads in areas of high human footprint, indicating reduced avoidance during lockdowns. Overall, lockdowns rapidly altered some spatial behaviors, highlighting variable but substantial impacts of human mobility on wildlife worldwide.