RNA-Dependent Epigenetic Silencing Directs Transcriptional Downregulation Caused by Intronic Repeat Expansions.

Transcriptional downregulation caused by intronic triplet repeat expansions underlies diseases such as Friedreich's ataxia. This downregulation of gene expression is coupled with epigenetic changes, but the underlying mechanisms are unknown. Here, we show that an intronic GAA/TTC triplet expansion within the IIL1 gene of Arabidopsis thaliana results in accumulation of 24-nt short interfering RNAs (siRNAs) and repressive histone marks at the IIL1 locus, which in turn causes its transcriptional downregulation and an associated phenotype. Knocking down DICER LIKE-3 (DCL3), which produces 24-nt siRNAs, suppressed transcriptional downregulation of IIL1 and the triplet expansion-associated phenotype. Furthermore, knocking down additional components of the RNA-dependent DNA methylation (RdDM) pathway also suppressed both transcriptional downregulation of IIL1 and the repeat expansion-associated phenotype. Thus, our results show that triplet repeat expansions can lead to local siRNA biogenesis, which in turn downregulates transcription through an RdDM-dependent epigenetic modification.

A warm Neptune's methane reveals core mass and vigorous atmospheric mixing.

Observations of transiting gas giant exoplanets have revealed a pervasive depletion of methane1-4, which has only recently been identified atmospherically5,6. The depletion is thought to be maintained by disequilibrium processes such as photochemistry or mixing from a hotter interior7-9. However, the interiors are largely unconstrained along with the vertical mixing strength and only upper limits on the CH4 depletion have been available. The warm Neptune WASP-107b stands out among exoplanets with an unusually low density, reported low core mass10, and temperatures amenable to CH4, though previous observations have yet to find the molecule2,4. Here we present a JWST-NIRSpec transmission spectrum of WASP-107b that shows features from both SO2 and CH4 along with H2O, CO2, and CO. We detect methane with 4.2σ significance at an abundance of 1.0 ± 0.5 ppm, which is depleted by 3 orders of magnitude relative to equilibrium expectations. Our results are highly constraining for the atmosphere and interior, which indicate the envelope has a super-solar metallicity of 43 ± 8 × solar, a hot interior with an intrinsic temperature of Tint = 460 ± 40 K, and vigorous vertical mixing which depletes CH4 with a diffusion coefficient of Kzz = 1011.6±0.1 cm2 s-1. Photochemistry has a negligible effect on the CH4 abundance but is needed to account for the SO2. We infer a core mass of 11.5 - 3.6 + 3.0 M ⊕ , which is much higher than previous upper limits10, releasing a tension with core-accretion models11.

Enhancing plant biotechnology by nanoparticle delivery of nucleic acids.

Plant biotechnology plays a crucial role in developing modern agriculture and plant science research. However, the delivery of exogenous genetic material into plants has been a long-standing obstacle. Nanoparticle-based delivery systems are being established to address this limitation and are proving to be a feasible, versatile, and efficient approach to facilitate the internalization of functional RNA and DNA by plants. The nanoparticle-based delivery systems can also be designed for subcellular delivery and controlled release of the biomolecular cargo. In this review, we provide a concise overview of the recent advances in nanocarriers for the delivery of biomolecules into plants, with a specific focus on applications to enhance RNA interference, foreign gene transfer, and genome editing in plants.

Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers.

PD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a 'barcode' to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein-Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.

Persistence of a Skewed Repertoire of NK Cells in People with HIV-1 on Long-Term Antiretroviral Therapy.

HIV-1 infection greatly alters the NK cell phenotypic and functional repertoire. This is highlighted by the expansion of a rare population of FcRγ- NK cells exhibiting characteristics of traditional immunologic memory in people with HIV (PWH). Although current antiretroviral therapy (ART) effectively controls HIV-1 viremia and disease progression, its impact on HIV-1-associated NK cell abnormalities remains unclear. To address this, we performed a longitudinal analysis detailing conventional and memory-like NK cell characteristics in n = 60 PWH during the first 4 y of ART. Throughout this regimen, a skewed repertoire of cytokine unresponsive FcRγ- memory-like NK cells persisted and accompanied an overall increase in NK surface expression of CD57 and KLRG1, suggestive of progression toward immune senescence. These traits were linked to elevated serum inflammatory biomarkers and increasing Ab titers to human CMV, with human CMV viremia detected in approximately one-third of PWH at years 1-4 of ART. Interestingly, 40% of PWH displayed atypical NK cell subsets, representing intermediate stages of NK-poiesis based on single-cell multiomic trajectory analysis. Our findings indicate that NK cell irregularities persist in PWH despite long-term ART, underscoring the need to better understand the causative mechanisms that prevent full restoration of immune health in PWH.

Interaction of Cardiovascular Nonmodifiable Risk Factors, Comorbidities and Comedications With Ischemia/Reperfusion Injury and Cardioprotection by Pharmacological Treatments and Ischemic Conditioning.

Preconditioning, postconditioning, and remote conditioning of the myocardium enhance the ability of the heart to withstand a prolonged ischemia/reperfusion insult and the potential to provide novel therapeutic paradigms for cardioprotection. While many signaling pathways leading to endogenous cardioprotection have been elucidated in experimental studies over the past 30 years, no cardioprotective drug is on the market yet for that indication. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic preclinical evaluation of promising cardioprotective therapies prior to their clinical evaluation, since ischemic heart disease in humans is a complex disorder caused by or associated with cardiovascular risk factors and comorbidities. These risk factors and comorbidities induce fundamental alterations in cellular signaling cascades that affect the development of ischemia/reperfusion injury and responses to cardioprotective interventions. Moreover, some of the medications used to treat these comorbidities may impact on cardioprotection by again modifying cellular signaling pathways. The aim of this article is to review the recent evidence that cardiovascular risk factors as well as comorbidities and their medications may modify the response to cardioprotective interventions. We emphasize the critical need for taking into account the presence of cardiovascular risk factors as well as comorbidities and their concomitant medications when designing preclinical studies for the identification and validation of cardioprotective drug targets and clinical studies. This will hopefully maximize the success rate of developing rational approaches to effective cardioprotective therapies for the majority of patients with multiple comorbidities. SIGNIFICANCE STATEMENT: Ischemic heart disease is a major cause of mortality; however, there are still no cardioprotective drugs on the market. Most studies on cardioprotection have been undertaken in animal models of ischemia/reperfusion in the absence of comorbidities; however, ischemic heart disease develops with other systemic disorders (e.g., hypertension, hyperlipidemia, diabetes, atherosclerosis). Here we focus on the preclinical and clinical evidence showing how these comorbidities and their routine medications affect ischemia/reperfusion injury and interfere with cardioprotective strategies.

Combinatorial treatment with exercise and AICAR potentiates the rescue of myotonic dystrophy type 1 mouse muscles in a sex-specific manner.

Targeting AMP-activated protein kinase (AMPK) is emerging as a promising strategy for treating myotonic dystrophy type 1 (DM1), the most prevalent form of adult-onset muscular dystrophy. We previously demonstrated that 5-aminomidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR) and exercise, two potent AMPK activators, improve disease features in DM1 mouse skeletal muscles. Here, we employed a combinatorial approach with these AMPK activators and examined their joint impact on disease severity in male and female DM1 mice. Our data reveal that swimming exercise additively enhances the effect of AICAR in mitigating the nuclear accumulation of toxic CUGexp RNA foci. In addition, our findings show a trend towards an enhanced reversal of MBNL1 sequestration and correction in pathogenic alternative splicing events. Our results further demonstrate that the combinatorial impact of exercise and AICAR promotes muscle fiber hypertrophy in DM1 skeletal muscle. Importantly, these improvements occur in a sex-specific manner with greater benefits observed in female DM1 mice. Our findings demonstrate that combining AMPK-activating interventions may prove optimal for rescuing the DM1 muscle phenotype and uncover important sex differences in the response to AMPK-based therapeutic strategies in DM1 mice.

Valvular Heart Disease: New Concepts in Pathophysiology and Therapeutic Approaches.

This review discusses recent advancements in the field of valvular heart disease. Topics covered include recognition of the impact of atrial fibrillation on development and assessment of valvular disease, strategies for global prevention of rheumatic heart disease, understanding and management of secondary mitral regurgitation, the updated classification of bicuspid aortic valve disease, recognition of heightened cardiovascular risk associated with moderate aortic stenosis, and a growing armamentarium of transcatheter therapies.

Inflammatory risk and cardiovascular events in patients without obstructive coronary artery disease: the ORFAN multicentre, longitudinal cohort study.

BACKGROUND: Coronary computed tomography angiography (CCTA) is the first line investigation for chest pain, and it is used to guide revascularisation. However, the widespread adoption of CCTA has revealed a large group of individuals without obstructive coronary artery disease (CAD), with unclear prognosis and management. Measurement of coronary inflammation from CCTA using the perivascular fat attenuation index (FAI) Score could enable cardiovascular risk prediction and guide the management of individuals without obstructive CAD. The Oxford Risk Factors And Non-invasive imaging (ORFAN) study aimed to evaluate the risk profile and event rates among patients undergoing CCTA as part of routine clinical care in the UK National Health Service (NHS); to test the hypothesis that coronary arterial inflammation drives cardiac mortality or major adverse cardiac events (MACE) in patients with or without CAD; and to externally validate the performance of the previously trained artificial intelligence (AI)-Risk prognostic algorithm and the related AI-Risk classification system in a UK population. METHODS: This multicentre, longitudinal cohort study included 40 091 consecutive patients undergoing clinically indicated CCTA in eight UK hospitals, who were followed up for MACE (ie, myocardial infarction, new onset heart failure, or cardiac death) for a median of 2·7 years (IQR 1·4-5·3). The prognostic value of FAI Score in the presence and absence of obstructive CAD was evaluated in 3393 consecutive patients from the two hospitals with the longest follow-up (7·7 years [6·4-9·1]). An AI-enhanced cardiac risk prediction algorithm, which integrates FAI Score, coronary plaque metrics, and clinical risk factors, was then evaluated in this population. FINDINGS: In the 2·7 year median follow-up period, patients without obstructive CAD (32 533 [81·1%] of 40 091) accounted for 2857 (66·3%) of the 4307 total MACE and 1118 (63·7%) of the 1754 total cardiac deaths in the whole of Cohort A. Increased FAI Score in all the three coronary arteries had an additive impact on the risk for cardiac mortality (hazard ratio [HR] 29·8 [95% CI 13·9-63·9], p<0·001) or MACE (12·6 [8·5-18·6], p<0·001) comparing three vessels with an FAI Score in the top versus bottom quartile for each artery. FAI Score in any coronary artery predicted cardiac mortality and MACE independently from cardiovascular risk factors and the presence or extent of CAD. The AI-Risk classification was positively associated with cardiac mortality (6·75 [5·17-8·82], p<0·001, for very high risk vs low or medium risk) and MACE (4·68 [3·93-5·57], p<0·001 for very high risk vs low or medium risk). Finally, the AI-Risk model was well calibrated against true events. INTERPRETATION: The FAI Score captures inflammatory risk beyond the current clinical risk stratification and CCTA interpretation, particularly among patients without obstructive CAD. The AI-Risk integrates this information in a prognostic algorithm, which could be used as an alternative to traditional risk factor-based risk calculators. FUNDING: British Heart Foundation, NHS-AI award, Innovate UK, National Institute for Health and Care Research, and the Oxford Biomedical Research Centre.

Long-read assembly and comparative evidence-based reanalysis of Cryptosporidium genome sequences reveal expanded transporter repertoire and duplication of entire chromosome ends including subtelomeric regions.

Cryptosporidiosis is a leading cause of waterborne diarrheal disease globally and an important contributor to mortality in infants and the immunosuppressed. Despite its importance, the Cryptosporidium community has only had access to a good, but incomplete, Cryptosporidium parvum IOWA reference genome sequence. Incomplete reference sequences hamper annotation, experimental design, and interpretation. We have generated a new C. parvum IOWA genome assembly supported by Pacific Biosciences (PacBio) and Oxford Nanopore long-read technologies and a new comparative and consistent genome annotation for three closely related species: C. parvum, Cryptosporidium hominis, and Cryptosporidium tyzzeri We made 1926 C. parvum annotation updates based on experimental evidence. They include new transporters, ncRNAs, introns, and altered gene structures. The new assembly and annotation revealed a complete Dnmt2 methylase ortholog. Comparative annotation between C. parvum, C. hominis, and C. tyzzeri revealed that most "missing" orthologs are found, suggesting that the biological differences between the species must result from gene copy number variation, differences in gene regulation, and single-nucleotide variants (SNVs). Using the new assembly and annotation as reference, 190 genes are identified as evolving under positive selection, including many not detected previously. The new C. parvum IOWA reference genome assembly is larger, gap free, and lacks ambiguous bases. This chromosomal assembly recovers all 16 chromosome ends, 13 of which are contiguously assembled. The three remaining chromosome ends are provisionally placed. These ends represent duplication of entire chromosome ends including subtelomeric regions revealing a new level of genome plasticity that will both inform and impact future research.

When cardiovascular medicines should be discontinued.

An integral component of the practice of medicine is focused on the initiation of medications, based on clinical practice guidelines and underlying trial evidence, which usually test the addition of novel medications intended for life-long use in short-term clinical trials. Much less attention is given to the question of medication discontinuation, especially after a lengthy period of treatment, during which patients age gets older and diseases may either progress or new diseases may emerge. Given the paucity of data, clinical practice guidelines offer little to no guidance on when and how to deprescribe cardiovascular medications. Such decisions are often left to the discretion of clinicians, who, together with their patients, express concern of potential adverse effects of medication discontinuation. Even in the absence of adverse effects, the continuation of medications without any proven effect may cause harm due to drug-drug interactions, the emergence of polypharmacy, and additional preventable spending to already strained health systems. Herein, several cardiovascular medications or medication classes are discussed that in the opinion of this author group should generally be discontinued, either for the prevention of potential harm, for a lack of benefit, or for the availability of better alternatives.

A novel CARM1-HuR axis involved in muscle differentiation and plasticity misregulated in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is characterized by the loss of alpha motor neurons in the spinal cord and a progressive muscle weakness and atrophy. SMA is caused by loss-of-function mutations and/or deletions in the survival of motor neuron (SMN) gene. The role of SMN in motor neurons has been extensively studied, but its function and the consequences of its loss in muscle have also emerged as a key aspect of SMA pathology. In this study, we explore the molecular mechanisms involved in muscle defects in SMA. First, we show in C2C12 myoblasts, that arginine methylation by CARM1 controls myogenic differentiation. More specifically, the methylation of HuR on K217 regulates HuR levels and subcellular localization during myogenic differentiation, and the formation of myotubes. Furthermore, we demonstrate that SMN and HuR interact in C2C12 myoblasts. Interestingly, the SMA-causing E134K point mutation within the SMN Tudor domain, and CARM1 depletion, modulate the SMN-HuR interaction. In addition, using the Smn2B/- mouse model, we report that CARM1 levels are markedly increased in SMA muscles and that HuR fails to properly respond to muscle denervation, thereby affecting the regulation of its mRNA targets. Altogether, our results show a novel CARM1-HuR axis in the regulation of muscle differentiation and plasticity as well as in the aberrant regulation of this axis caused by the absence of SMN in SMA muscle. With the recent developments of therapeutics targeting motor neurons, this study further indicates the need for more global therapeutic approaches for SMA.

Management of Pericardial Effusion in Patients With Solid Tumor: An Algorithmic, Multidisciplinary Approach Results in Reduced Mortality After Paradoxical Hemodynamic Instability.

OBJECTIVE: This study compared outcomes in patients with solid tumor treated for pericardial effusion with surgical drainage versus interventional radiology (IR) percutaneous drainage and compared incidence of paradoxical hemodynamic instability (PHI) between cohorts. BACKGROUND: Patients with advanced-stage solid malignancies may develop large pericardial effusions requiring intervention. PHI is a fatal and underreported complication that occurs following pericardial effusion drainage. METHODS: Clinical characteristics and outcomes were compared between patients with solid tumors who underwent s urgical drainage or IR percutaneous drainage for pericardial effusion from 2010 to 2020. RESULTS: Among 447 patients, 243 were treated with surgical drainage, of which 27 (11%) developed PHI, compared with 7 of 204 patients (3%) who were treated with IR percutaneous drainage ( P =0.002); overall incidence of PHI decreased during the study period. Rates of reintervention (30-day: 1% vs 4%; 90-day: 4% vs 6%, P =0.7) and mortality (30-day: 21% vs 17%, P =0.3; 90-day: 39% vs 37%, P =0.7) were not different between patients treated with surgical drainage and IR percutaneous drainage. For both interventions, OS was shorter among patients with PHI than among patients without PHI (surgical drainage, median [95% confidence interval] OS, 0.89 mo [0.33-2.1] vs 6.5 mo [5.0-8.9], P <0.001; IR percutaneous drainage, 3.7 mo [0.23-6.8] vs 5.0 mo [4.0-8.1], P =0.044). CONCLUSIONS: With a coordinated multidisciplinary approach focusing on prompt clinical and echocardiographic evaluation, triage with bias toward IR percutaneous drainage than surgical drainage and postintervention intensive care resulted in lower incidence of PHI and improved outcomes.

A New Functional Threshold for Minimally Invasive Lobectomy.

OBJECTIVE: To assess the performance of a lower predicted postoperative (ppo) forced expiratory volume in 1 second (FEV1) or diffusion capacity of the lung for carbon monoxide (DLCO) (ppoFEV1/ppoDLCO) threshold to predict cardiopulmonary complications after minimally invasive surgery (MIS) lobectomy. SUMMARY BACKGROUND DATA: Although MIS is associated with better postoperative outcomes than open surgery, MIS uses risk-assessment algorithms developed for open surgery. Moreover, several different definitions of cardiopulmonary complications are used for assessment. METHODS: All patients who underwent MIS lobectomy for clinical stage I-II lung cancer from 2018 to 2022 at our institution were considered. The performance of a ppoFEV1/ppoDLCO threshold of <45% was compared against that of the current guideline threshold of <60%. Three different definitions of cardiopulmonary complications were compared: Society of Thoracic Surgeons (STS), European Society of Thoracic Surgeons (ESTS), and Berry et al. RESULTS: In 946 patients, the ppoFEV1/ppoDLCO threshold of <45% was associated with a higher proportion correctly classified (79% [95% CI, 76%-81%] vs. 65% [95% CI, 62%-68%]; P<0.001). The complication with the biggest difference in incidence between ppoFEV1/ppoDLCO of 45%-60% and >60% was prolonged air leak (33 [13%] vs. 34 [6%]; P<0.001). The predicted probability curves for cardiopulmonary complications were higher for the STS definition than for the ESTS or Berry definitions across ppoFEV1 and ppoDLCO values. CONCLUSIONS: The ppoFEV1/ppoDLCO threshold of <45% more accurately classified patients for cardiopulmonary complications after MIS lobectomy, emphasizing the need for updated risk-assessment guidelines for MIS lobectomy to optimize additional cardiopulmonary function evaluation.

Effects of cavity nonlinearities and linear losses on silicon microring-based reservoir computing.

Microring resonators (MRRs) are promising devices for time-delay photonic reservoir computing, but the impact of the different physical effects taking place in the MRRs on the reservoir computing performance is yet to be fully understood. We numerically analyze the impact of linear losses as well as thermo-optic and free-carrier effects relaxation times on the prediction error of the time-series task NARMA-10. We demonstrate the existence of three regions, defined by the input power and the frequency detuning between the optical source and the microring resonance, that reveal the cavity transition from linear to nonlinear regimes. One of these regions offers very low error in time-series prediction under relatively low input power and number of nodes while the other regions either lack nonlinearity or become unstable. This study provides insight into the design of the MRR and the optimization of its physical properties for improving the prediction performance of time-delay reservoir computing.

Study Partner Report of Apathy in Older Adults is Associated with AD Biomarkers: Findings from the Harvard Aging Brain Study.

OBJECTIVES: We examined relationships between apathy (self and study-partner-reported) and markers of Alzheimer's disease (AD) in older adults. DESIGN: The study utilized a well-characterized sample of participants from the Harvard Aging Brain Study (HABS), a longitudinal cohort study. Participants were cognitively unimpaired without clinically significant neuropsychiatric symptoms at HABS baseline. The dependent variables, apathy evaluation scale-self (AES-S) and informant (AES-I), were administered cross-sectionally between years 6-9 and compared to the independent variables, amyloid and tau PET neuroimaging, from the same year. SETTING: Community-dwelling participants assessed at research visits in an academic medical center. PARTICIPANTS: Participants (n = 170) completed assessments within 1.5 years of their neuroimaging visit. At the time of apathy assessment, N = 156 were cognitively unimpaired and 14 had progressed to mild cognitive impairment (n = 8) or dementia (n = 6). MEASUREMENTS: We utilized linear regression models to assess cross-sectional associations of AES-S and AES-I with AD PET imaging measures (beta-amyloid (Pittsburgh Compound B) and tau (Flortaucipir)), covarying for age, sex, education, and the time between PET scan-apathy assessment. RESULTS: AES-I was significantly associated with beta-amyloid and temporal lobe tau, and the associations were retained after further adjusting for depressive symptoms. The associations between AES-S and AD biomarkers were not significant. In an exploratory subgroup analysis of cognitively unimpaired individuals with elevated Aß, we observed an association between AES-I and inferior temporal tau. CONCLUSIONS: Study-partner-reported, but not self-reported, apathy in older adults is associated with AD pathology, and we observed this relationship starting from the preclinical stage. Our findings highlight the importance of collateral information in capturing AD-related apathy.

Constrictive versus compressive bladder outflow obstruction in men: Does it matter?

INTRODUCTION: Bladder outflow obstruction (BOO) is a urethral resistance (UR) at a level above a clinically relevant threshold. UR is currently graded in terms of the existence and severity of the BOO based on maximum flowrate and associated detrusor pressure only. However, the pressure-flow relation throughout the course of voiding includes additional information that may be relevant to identify the type of BOO. This study introduces a new method for the distinction between the provisionally called compressive and constrictive types of BOO and relates this classification to underlying patient and urodynamic differences between those BOO types. METHODS: In total, 593 high-quality urodynamic pressure-flow studies in men were included in this study. Constrictive BOO was identified if the difference Δp between the actual minimal urethral opening pressure (pmuo) and the expected pmuo according to the linearized passive urethral resistance relation (linPURR) nomogram was >25 cmH2O. Compressive BOO is identified in the complementary case where the pressure difference Δp ≤ 25 cmH2O. Differences in urodynamic parameters, patient age, and prostate size were explored. RESULTS: In 81 (13.7%) of the cases, constrictive BOO was found. In these patients, the prostate size was significantly smaller when compared to patients diagnosed with compressive BOO, while displaying a significantly lower maximum flowrate, higher detrusor pressure at maximal flowrate and more postvoid residual (PVR). CONCLUSION: This study is an initial step in the validation of additional subtyping of BOO. We found significant differences in prostate size, severity of BOO, and PVR, between patients with compressive and constrictive BOO. Subtyping of voiding-outflow dynamics may lead to more individualized management in patients with BOO.

The Roots of Science, Technology, Engineering, and Mathematics: What Are the Evolutionary and Neural Bases of Human Mathematics and Technology?

INTRODUCTION: Neural exaptations represent descent via transitions to novel neural functions. A primary transition in human cognitive and neural evolution was from a predominantly socially oriented primate brain to a brain that also instantiates and subserves science, technology, and engineering, all of which depend on mathematics. Upon what neural substrates and upon what evolved cognitive mechanisms did human capacities for science, technology, engineering, and mathematics (STEM), and especially its mathematical underpinnings, emerge? Previous theory focuses on roles for tools, language, and arithmetic in the cognitive origins of STEM, but none of these factors appears sufficient to support the transition. METHODS: In this article, I describe and evaluate a novel hypothesis for the neural origins and substrates of STEM-based cognition: that they are based in human kinship systems and human maximizing of inclusive fitness. RESULTS: The main evidence for this hypothesis is threefold. First, as demonstrated by anthropologists, human kinship systems exhibit complex mathematical and geometrical structures that function under sets of explicit rules, and such systems and rules pervade and organize all human cultures. Second, human kinship underlies the core algebraic mechanism of evolution, maximization of inclusive fitness, quantified as personal reproduction plus the sum of all effects on reproduction of others, each multiplied by their coefficient of relatedness to self. This is the only "natural" equation expected to be represented in the human brain. Third, functional imaging studies show that kinship-related cognition activates frontal-parietal regions that are also activated in STEM-related tasks. In turn, the decision-making that integrates kinship levels with costs and benefits from alternative behaviors has recently been shown to recruit the lateral septum, a hub region that combines internal (from the prefrontal cortex, amygdala, and other regions) and external information relevant to social behavior, using a dedicated subsystem of neurons specific to kinship. CONCLUSIONS: Taken together, these lines of evidence suggest that kinship systems and kin-associated behaviors may represent exaptations for the origin of human STEM.

Determinants of radiation exposure during mobile cone-beam CT-guided robotic-assisted bronchoscopy.

BACKGROUND AND OBJECTIVE: Robotic-assisted bronchoscopy (RAB) is an emerging modality to sample pulmonary lesions. Cone-beam computed tomography (CBCT) can be incorporated into RAB. We investigated the magnitude and predictors of patient and staff radiation exposure during mobile CBCT-guided shape-sensing RAB. METHODS: Patient radiation dose was estimated by cumulative dose area product (cDAP) and cumulative reference air kerma (cRAK). Staff equivalent dose was calculated based on isokerma maps and a phantom simulation. Patient, lesion and procedure-related factors associated with higher radiation doses were identified by logistic regression models. RESULTS: A total of 198 RAB cases were included in the analysis. The median patient cDAP and cRAK were 10.86 Gy cm2 (IQR: 4.62-20.84) and 76.20 mGy (IQR: 38.96-148.38), respectively. Among staff members, the bronchoscopist was exposed to the highest median equivalent dose of 1.48 µSv (IQR: 0.85-2.69). Both patient and staff radiation doses increased with the number of CBCT spins and targeted lesions (p < 0.001 for all comparisons). Patient obesity, negative bronchus sign, lesion size <2.0 cm and inadequate sampling by on-site evaluation were associated with a higher patient dose, while patient obesity and inadequate sampling by on-site evaluation were associated with a higher bronchoscopist equivalent dose. CONCLUSION: The magnitude of patient and staff radiation exposure during CBCT-RAB is aligned with safety thresholds recommended by regulatory authorities. Factors associated with a higher radiation exposure during CBCT-RAB can be identified pre-operatively and solicit procedural optimization by reinforcing radiation protective measures. Future studies are needed to confirm these findings across multiple institutions and practices.

Staufen1 controls mitochondrial metabolism via HIF2α in embryonal rhabdomyosarcoma and promotes tumorigenesis.

Elevated mitochondrial metabolism promotes tumorigenesis of Embryonal Rhabdomyosarcomas (ERMS). Accordingly, targeting oxidative phosphorylation (OXPHOS) could represent a therapeutic strategy for ERMS. We previously demonstrated that genetic reduction of Staufen1 (STAU1) levels results in the inhibition of ERMS tumorigenicity. Here, we examined STAU1-mediated mechanisms in ERMS and focused on its potential involvement in regulating OXPHOS. We report the novel and differential role of STAU1 in mitochondrial metabolism in cancerous versus non-malignant skeletal muscle cells (NMSkMCs). Specifically, our data show that STAU1 depletion reduces OXPHOS and inhibits proliferation of ERMS cells. Our findings further reveal the binding of STAU1 to several OXPHOS mRNAs which affects their stability. Indeed, STAU1 depletion reduced the stability of OXPHOS mRNAs, causing inhibition of mitochondrial metabolism. In parallel, STAU1 depletion impacted negatively the HIF2α pathway which further modulates mitochondrial metabolism. Exogenous expression of HIF2α in STAU1-depleted cells reversed the mitochondrial inhibition and induced cell proliferation. However, opposite effects were observed in NMSkMCs. Altogether, these findings revealed the impact of STAU1 in the regulation of mitochondrial OXPHOS in cancer cells as well as its differential role in NMSkMCs. Overall, our results highlight the therapeutic potential of targeting STAU1 as a novel approach for inhibiting mitochondrial metabolism in ERMS.