Background: TERT promoter mutation (TPM) is an established biomarker in meningiomas associated with aberrant TERT expression and reduced progression-free survival (PFS). TERT expression, however, has also been observed even in tumours with wildtype TERT promoters (TP-WT). This study aimed to examine TERT expression and clinical outcomes in meningiomas. Methods: TERT expression, TPM status, and TERT promoter methylation of a multi-institutional cohort of meningiomas (n=1241) was assessed through nulk RNA sequencing (n=604), Sanger sequencing of the promoter (n=1095), and methylation profiling (n=1218). 380 Toronto meningiomas were used for discovery, and 861 external institution samples were compiled as a validation cohort. Results: Both TPMs and TERTpromoter methylation were associated with increased TERT expression and may represent independent mechanisms of TERT reactivation. TERT expression was detected in 30.4% of meningiomas that lacked TPMs, was associated with higher WHO grades, and corresponded to shorter PFS, independent of grade and even among TP-WT tumours. TERT expression was associated with a shorter PFS equivalent to those of TERT-negative meningiomas of one higher grade. Conclusions: Our findings highlight the prognostic significance of TERT expression in meningiomas, even in the absence of TPMs. Its presence may identify patients who may progress earlier and should be considered in risk stratification models.

Recently, subcritical transition to turbulence in the quasi-two-dimensional (quasi-2-D) shear flow with strong linear friction (Camobreco et al., J. Fluid Mech., vol. 963, 2023, R2) has been demonstrated by the 2-D mechanism at $Re = 71\,211$, and the nonlinear Tollmien–Schlichting (TS) waves related to the edge state were approached independently of initial optimal disturbances. For 2-D plane Poiseuille flow, transition to the fully developed turbulence requires that the Reynolds number is several times larger than the critical Reynolds number $Re_c$ (Markeviciute & Kerswell, J. Fluid Mech., vol. 917, 2021, A57). In this paper, we observed the subcritical transitional flow in 2-D plane Poiseuille flow driven by the nonlinear TS waves by both linear and nonlinear optimal disturbances ($Re < Re_c$) with different quantitative edge states. The nonlinear optimal disturbances could trigger the sustained subcritical transitional flow for $Re \geqslant 2400$. The initial energy for nonlinear optimal disturbance is more efficient than the linear optimal disturbance in reaching the subcritical transitional flow for $2400 \leqslant Re \leqslant 5000$. Moreover, the initial energy of linear optimal disturbance is larger than the energy of its edge state. The nonlinear TS waves along the edge state are formed by the nonlinear optimal disturbances to trigger transitional flow, which agrees well with the main conclusions of Camobreco et al. (J. Fluid Mech., vol. 963, 2023, R2), while the required $Re$ of 2-D plane Poiseuille flow is much smaller.

The increasing demands for oil and gas and associated difficult drilling operations require oil-based drilling fluids that possess excellent rheological properties and thermal stability. The objective of the present work was to investigate the rheological properties and thermal stability of organo-montmorillonite (OMnt) modified with various surfactants and under various loading levels in oil-based drilling fluids, as revealed by the interaction between organic surfactants and montmorillonite. The influence of the structural arrangement of surfactants on the thermal stability of organo-montmorillonite (OMnt) in oil-based drilling fluids was also addressed. OMnt samples were prepared in aqueous solution using surfactants possessing either a single long alkyl chain two long alkyl chains. OMnt samples were characterized by X-ray diffraction, high-resolution transmission electron microscopy, thermal analysis, and X-ray photoelectron spectroscopy. Organic surfactants interacted with montmorillonite by electrostatic attraction. The arrangements of organic surfactants depended on the number of long alkyl chains and the geometrical shape of organic cations. In addition to the thermal stability of surfactants, intermolecular interaction also improved the thermal stability of OMnt/oil fluids. A tight paraffin-type bilayer arrangement contributed to the excellent rheological properties and thermal stability of OMnt/oil fluids. The deterioration of rheological properties of OMnt/oil fluids at temperatures up to 200°C was due mainly to the release of interlayer surfactants into the oil.

In the Spring of 2020, the onset of the global pandemic intensified existing inequalities, but also accelerated organizing within some of the most precarious economic sectors. The neoliberal university was no exception to this general trend, and from 2020 until 2022, student workers organized for union contracts, just pandemic responses, independent arbitration for harassment and improved conditions at their workplaces. In those years, while neoliberal universities issued empty calls for “community,” and a prompt return to normalcy, student workers mobilized themselves and won unprecedented gains from their institutions, rejecting administrative pleas for the defense of the status quo. The following “Report from the Field,” details the struggle of student workers organizing from 2020 to 2022 at the University of New Mexico, the University of Michigan, New York University, and Columbia University, and offers a collectively authored reflection on the challenges, victories and future concerns of its respective movements.

Background: In meningiomas, CDKN2A/B deletions are associated with poor outcomes but are rare in most cohorts (1-5%). Large molecular datasets are therefore required to explore these deletions and their relationship to other prognostic CDKN2A alterations. Methods: We utilized multidimensional molecular data of 560 meningiomas from 5 independent cohorts to comprehensively interrogate the spectrum of CDKN2A alterations through DNA methylation, copy number variation, transcriptomics, and proteomics using an integrated molecular approach. Results: Meningiomas with either CDKN2A/B deletions (partial or homozygous loss) or an intact CDKN2A gene locus but elevated mRNA expression (CDKN2Ahigh) both had poor clinical outcomes. Increased CDKN2A mRNA expression was a poor prognostic factor independent of CDKN2A deletion. CDKN2A expression and p16 protein increased with tumor grade and more aggressive molecular and methylation groups. CDKN2Ahigh meningiomas and meningiomas with CDKN2A deletions were enriched for similar cell cycling pathways dysregulated at different checkpoints. p16 immunohistochemistry was unreliable in differentiating between meningiomas with and without CDKN2A deletions, but increased positivity was associated with increased mRNA expression. CDKN2Ahigh meningiomas were associated with gene hypermethylation, Rb-deficiency, and lack of response to CDK inhibition. Conclusions: These findings support the role of CDKN2A mRNA expression as a biomarker of clinically aggressive meningiomas with potential therapeutic implications.

OBJECTIVES/GOALS: Our long-term goal is to understand how both genetic and environmental (GxE) factors contribute to neurodevelopmental disorders (NDDs) so that we may potentially intervene in disease pathogenesis and design therapies to address functional deficiencies. METHODS/STUDY POPULATION: Our studies use a novel GxE model to determine how cephalosporin antibiotic exposure alters the gut microbiome, hippocampal neurogenesis, and behavior in the genetically vulnerable 16p11.2 microdeletion (16pDel) mouse. This mouse models one of the most frequently observed genetic risk variants implicated in NDDs, including ~1% of autism diagnoses. Wildtype and 16pDel littermates were exposed to saline or the cephalosporin, cefdinir, from postnatal days 5-9. We quantified changes in gut microbiota composition using 16S rRNA gene sequencing and utilized immunoblotting, immunohistochemistry, and bulk RNA gene sequencing to assess changes in hippocampal neurogenesis. An additional cohort of saline or cefdinir-exposed mice were subjected to a behavioral battery to assess changes in sociability and anxiety. RESULTS/ANTICIPATED RESULTS: We leveraged the next-generation microbiome bioinformatics platform, Quantitative Insights Into Microbial Ecology 2 (QIIME2) to analyze 16S rRNA gene sequencing datasets of P13 cecal samples from saline- and cefdinir-exposed mice. We found successful perturbations to the gut microbiome following early life cefdinir exposure. Further, we found a robust 50% reduction in hippocampal cyclin E protein in cefdinir-exposed 16pDel male mice, which was replicated in a second independent experiment. This reduction extended to the S-phase cell entry and general stem cell population, quantified by EdU+ and Ki67+ cell numbers, respectively. Lastly, in our first cohort of mice for behavioral studies, we found reduced sociability and increased anxiety-like behaviors in cefdinir-exposed mice. DISCUSSION/SIGNIFICANCE: The findings from this GxE model will provide mechanistic insights into the causes of NDDs; they may inform practice guidelines so as to reduce this environmental exposure; and may suggest interventions like probiotics for those at risk in order to overcome altered gut microbiome composition and restore hippocampal neurogenesis defects.

The hawksbill sea turtle Eretmochelys imbricata is categorized as Critically Endangered on the IUCN Red List and its population has declined by over 80% in the last century. The Eastern Pacific population is one of the most threatened hawksbill populations globally. Western Mexico is the northern distribution limit for hawksbill sea turtles in the Eastern Pacific and recent research indicates that the Mexican Pacific portion of the population is a separate management unit because of the restricted movements of these turtles. Here we use the most complete database of sighting records in the north-west Pacific of Mexico to identify sites where hawksbill turtles are present. We also develop a conservation index to determine the conservation status of hawksbill turtle sites. Our results demonstrate the importance of this region for juveniles and the relevance of rocky reefs and mangrove estuaries as habitats for hawksbill turtles. We identified 52 sites with records of hawksbill turtles. Most of these sites (71%) are not protected; however, sites with high conservation value included islands and coastal sites along the Baja California peninsula that are established as marine protected areas. Reefs and mangrove estuaries relevant for hawksbill turtles are probably also significant fish nursery areas that are important for local fishing communities, creating opportunities for conservation strategies that combine science, local engagement and policy to benefit both local fishing communities and hawksbill sea turtle conservation.

Patients with Duchenne muscular dystrophy have multiple risk factors for lower extremity oedema. This study sought to define the frequency and predictors of oedema. Patients aged 15 years and older were screened by patient questionnaire, and the presence of oedema was confirmed by subsequent physical exam. Twenty-four of 52 patients (46%) had oedema, 12 of whom had swelling extending above the foot and two with sores/skin breakdown. There was no significant difference in age, frequency, or duration of glucocorticoid use, non-invasive respiratory support use, forced vital capacity, cardiac medication use, or ejection fraction between patients with and without oedema (all p > 0.2). Those with oedema had a greater time since the loss of ambulation (8.4 years versus 3.5 years; p = 0.004), higher body mass index (28.3 versus 24.8; p = 0.014), and lower frequency of deflazacort use (67% versus 89%; p = 0.008). Multivariate analysis revealed a longer duration of loss of ambulation (p = 0.02) and higher body mass index (p = 0.009) as predictors of oedema. Lower extremity oedema is common in Duchenne muscular dystrophy but independent of cardiac function. Interventions focused on minimising body mass index increases over time may be a therapeutic target.

The 4.2 ka event is widely presumed to be a globally widespread aridity event and has been linked to several episodes of societal changes across the globe. Whether this climate event impacted the cultural development in south-central China remains uncertain due to a lack of regional paleorainfall records. We present here stalagmite stable carbon isotope and trace element–based reconstruction of hydroclimatic conditions from south-central China. Our data reveal a sub–millennial scale (~5.6 to 4.3 ka) drying trend in the region followed by a gradual transition to wetter conditions during the 4.2 ka event (4.3–3.9 ka). Together with the existing archaeological evidence, our data suggest that the drier climate before 4.3 ka may have promoted the Shijiahe culture, while the pluvial conditions during the 4.2 ka event may have adversely affected its settlements in low-lying areas. While military conflicts with the Wangwan III culture may have accelerated the collapse of Shijiahe culture, we suggest that the joint effects of climate and the region's topography also played important causal roles in its demise.

Manure is a primary source of methane (CH4) emissions into the atmosphere. A large proportion of CH4 from manure is emitted during storage, but this varies with storage methods. In this research, we tested whether covering a manure heap with plastic reduces CH4 emission during a short-term composting process. A static chamber method was used to detect the CH4 emission rate and the change of the physicochemical properties of cattle manure which was stored either uncovered (treatment UNCOVERED) or covered with plastic (treatment COVERED) for 30-day periods during the four seasons? The dry matter content of the COVERED treatment was significantly less than the UNCOVERED treatment (P < 0.01), and the C/N ratio of the COVERED treatment significantly greater than the UNCOVERED treatment (P > 0.05) under high temperature. In the UNCOVERED treatment, average daily methane (CH4) emissions were in the order summer > spring > autumn > winter. CH4 emissions were positively correlated with the temperature (R2 = 0.52, P < 0.01). Compared to the UNCOVERED treatment, the daily average CH4 emission rates from COVERED treatment manure were less in the first 19 days of spring, 13 days of summer, 10 days of autumn and 30 days of winter. In summary, covering the manure pile with plastic reduces the evaporation of water during storage; and in winter, long-term covering with plastic film reduces the CH4 emissions during the storage of manure.

We examined whether Research Domain Criteria (RDoC)-informed measures of prenatal stress predicted newborn neurobehavior and whether these effects differed by newborn sex. Multilevel, prenatal markers of prenatal stress were obtained from 162 pregnant women. Markers of the Negative Valence System included physiological functioning (respiratory sinus arrhythmia [RSA] and electrodermal [EDA] reactivity to a speech task, hair cortisol), self-reported stress (state anxiety, pregnancy-specific anxiety, daily stress, childhood trauma, economic hardship, and family resources), and interviewer-rated stress (episodic stress, chronic stress). Markers of the Arousal/Regulatory System included physiological functioning (baseline RSA, RSA, and EDA responses to infant cries) and self-reported affect intensity, urgency, emotion regulation strategies, and dispositional mindfulness. Newborns’ arousal and attention were assessed via the Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scale. Path analyses showed that high maternal episodic and daily stress, low economic hardship, few emotion regulation strategies, and high baseline RSA predicted female newborns’ low attention; maternal mindfulness predicted female newborns’ high arousal. As for male newborns, high episodic stress predicted low arousal, and high pregnancy-specific anxiety predicted high attention. Findings suggest that RDoC-informed markers of prenatal stress could aid detection of variance in newborn neurobehavioral outcomes within hours after birth. Implications for intergenerational transmission of risk for psychopathology are discussed.