Molecular evolutionary time scales are expected to predate the fossil evidence, but, particularly for major evolutionary radiations, they can imply extremely protracted stem lineages predating the origin of living clades, leading to claims of systematic overestimation of divergence times. We use macroevolutionary birth death models to describe the range of total group and crown group ages expected under constant rates of speciation and extinction. We extend current predictions on origination times for crown and total groups, and extinction of stem groups, demonstrating that there is broad variance in these predictions. Under constant rates of speciation and extinction, we show that the distribution of expected arthropod total group ages is consistent with molecular clock estimates. The fossil record cannot be read literally, and our results preclude attempts to interpret the antiquity of clades based on the co occurrence of stem and crown representatives.
Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Approximately one-third of cases do not have a known genetic cause. Exome sequencing of 104 persons with congenital neutropenia identified heterozygous missense variants of CLPB (caseinolytic peptidase B) in 5 SCN cases, with 5 more cases identified through additional sequencing efforts or clinical sequencing. CLPB encodes an adenosine triphosphatase (ATPase) implicated in protein folding and mitochondrial function. Prior studies showed that biallelic mutations of CLPB are associated with a syndrome of 3-methylglutaconic aciduria, cataracts, neurologic disease, and variable neutropenia. However, 3-methylglutaconic aciduria was not observed and, other than neutropenia, these clinical features were uncommon in our series. Moreover, the CLPB variants are distinct, consisting of heterozygous variants that cluster near the ATP-binding pocket. Both genetic loss of CLPB and expression of CLPB variants results in impaired granulocytic differentiation of human hematopoietic progenitors and increased apoptosis. These CLPB variants associate with wildtype CLPB and inhibit its ATPase and disaggregase activity in a dominant-negative fashion. Finally, expression of CLPB variants is associated with impaired mitochondrial function but does not render cells more sensitive to endoplasmic reticulum stress. Together, these data show that heterozygous CLPB variants are a new and relatively common cause of congenital neutropenia and should be considered in the evaluation of patients with congenital neutropenia.
The mammalian SWI/SNF complex, or BAF complex, has a conserved and direct role in antagonizing Polycomb-mediated repression. Yet, BAF also promotes repression by Polycomb in stem cells and cancer. How BAF both antagonizes and promotes Polycomb-mediated repression remains unknown. Here, we utilize targeted protein degradation to dissect the BAF–Polycomb axis in mouse embryonic stem cells on short timescales. We report that rapid BAF depletion redistributes Polycomb repressive complexes PRC1 and PRC2 from highly occupied domains, like Hox clusters, to weakly occupied sites normally opposed by BAF. Polycomb redistribution from highly repressed domains results in their decompaction, gain of active epigenomic features and transcriptional derepression. Surprisingly, through dose-dependent degradation of PRC1 and PRC2, we identify a conventional role for BAF in Polycomb-mediated repression, in addition to global Polycomb redistribution. These findings provide new mechanistic insight into the highly dynamic state of the Polycomb–Trithorax axis.
Like so many in our academic community, we were distressed by the February 2021 JAMA podcast and corresponding tweet suggesting that structural racism does not exist and that no physicians are racist. Although we have not written about this issue until now, these events have prompted a deep internal reexamination of how we engage constructively to acknowledge and reverse structural racism and of our own contributions to perpetuating it. We are challenging ourselves to consider how we can be truly antiracist in our roles as physicians, scientists, editors, and members of the communities in which we work and live.
The current opioid epidemic warrants a better understanding of genetic and environmental factors that contribute to opioid addiction. Here we report an increased prevalence of vitamin D (VitD) deficiency in patients diagnosed with opioid use disorder and an inverse and dose dependent association of VitD levels with self reported opioid use. We used multiple pharmacologic approaches and genetic mouse models and found that deficiencies in VitD signaling amplify exogenous opioid responses that are normalized upon restoration of VitD signaling. Similarly, physiologic endogenous opioid analgesia and reward responses triggered by ultraviolet (UV) radiation are repressed by VitD signaling, suggesting that a feedback loop exists whereby VitD deficiency produces increased UV/endorphin seeking behavior until VitD levels are restored by cutaneous VitD synthesis. This feedback may carry the evolutionary advantage of maximizing VitD synthesis. However, unlike UV exposure, exogenous opioid use is not followed by VitD synthesis (and its opioid suppressive effects), contributing to maladaptive addictive behavior.
The library of two-dimensional (2D) materials has been enriched over recent years with novel crystal architectures endowed with diverse exciting functionalities. Bulk perovskites, including metal-halide and oxide systems, provide access to a myriad of properties through molecular engineering. Their tunable electronic structure offers remarkable features from long carrier-diffusion lengths and high absorption coefficients in metal-halide perovskites to high-temperature superconductivity, magnetoresistance and ferroelectricity in oxide perovskites. Emboldened by the 2D materials research, perovskites down to the monolayer limit have recently emerged. Like other 2D species, perovskites with reduced dimensionality are expected to exhibit new physics and to herald next-generation multifunctional devices. In this Review, we critically assess the preliminary studies on the synthetic routes and inherent properties of monolayer perovskite materials. We also discuss how to exploit them for widespread applications and provide an outlook on the challenges and opportunities that lie ahead for this enticing class of 2D materials.
Ecological theory is built on trade-offs, where trait differences among species evolved as adaptations to different environments. Trade-offs are often assumed to be bidirectional, where opposite ends of a gradient in trait values confer advantages in different environments. However, unidirectional benefits could be widespread if extreme trait values confer advantages at one end of an environmental gradient, whereas a wide range of trait values are equally beneficial at the other end. Here, we show that root traits explain species occurrences along broad gradients of temperature and water availability, but model predictions only resembled trade-offs in two out of 24 models. Forest species with low specific root length and high root tissue density (RTD) were more likely to occur in warm climates but species with high specific root length and low RTD were more likely to occur in cold climates. Unidirectional benefits were more prevalent than trade-offs: for example, species with large-diameter roots and high RTD were more commonly associated with dry climates, but species with the opposite trait values were not associated with wet climates. Directional selection for traits consistently occurred in cold or dry climates, whereas a diversity of root trait values were equally viable in warm or wet climates. Explicit integration of unidirectional benefits into ecological theory is needed to advance our understanding of the consequences of trait variation on species responses to environmental change.
Artificial intelligence (AI) represents a valuable tool that could be widely used to inform clinical and public health decision-making to effectively manage the impacts of a pandemic. The objective of this scoping review was to identify the key use cases for involving AI for pandemic preparedness and response from the peer-reviewed, preprint, and grey literature. The data synthesis had two parts: an in-depth review of studies that leveraged machine learning (ML) techniques and a limited review of studies that applied traditional modeling approaches. ML applications from the in-depth review were categorized into use cases related to public health and clinical practice, and narratively synthesized. One hundred eighty-three articles met the inclusion criteria for the in-depth review. Six key use cases were identified: forecasting infectious disease dynamics and effects of interventions; surveillance and outbreak detection; real-time monitoring of adherence to public health recommendations; real-time detection of influenza-like illness; triage and timely diagnosis of infections; and prognosis of illness and response to treatment. Data sources and types of ML that were useful varied by use case. The search identified 1167 articles that reported on traditional modeling approaches, which highlighted additional areas where ML could be leveraged for improving the accuracy of estimations or projections. Important ML-based solutions have been developed in response to pandemics, and particularly for COVID-19 but few were optimized for practical application early in the pandemic. These findings can support policymakers, clinicians, and other stakeholders in prioritizing research and development to support operationalization of AI for future pandemics.
The organs and metabolic pathways involved in energy metabolism, and the process of ATP production from nutrients, are comparable between humans and Drosophila melanogaster. This level of conservation, together with the power of Drosophila genetics, makes the fly a very useful model system to study energy homeostasis. Here, we discuss the major organs involved in energy metabolism in Drosophila and how they metabolize different dietary nutrients to generate adenosine triphosphate. Energy metabolism in these organs is controlled by cell intrinsic, paracrine, and endocrine signals that are similar between Drosophila and mammals. We describe how these signaling pathways are regulated by several physiological and environmental cues to accommodate tissue , age , and environment specific differences in energy demand. Last, we discuss several genetic and diet induced fly models of obesity and diabetes that can be leveraged to better understand the molecular basis of these metabolic diseases and thereby promote the development of novel therapies.
Journal of Pharmacy Practice, Ahead of Print. Background :Dexmedetomidine is a highly selective α2 adrenoreceptor agonist that produces dose dependent sedation, anxiolysis, and analgesia without respiratory depression. Due to these ideal sedative properties, there has been increased interest in utilizing dexmedetomidine as a first line sedative for critically ill patients requiring light sedation.Objective :To evaluate the ability to achieve goal intensive care unit (ICU) sedation before and after an institutional change of dosing from actual (ABW) to adjusted (AdjBW) body weight in obese patients on dexmedetomidine.Method :This study included patients ≥ 18 years old, admitted to a surgical or medical ICU, required dexmedetomidine for at least 8 hours as a single continuous infusion sedative, and weighed ≥ 120% of ideal body weight. Percentage of RASS measurements within goal range (−1 to +1) during the first 48 hours after initiation of dexmedetomidine as the sole sedative agent or until discontinuation dosed on ABW compared to AdjBW was evaluated.Result :100 patients were included in the ABW cohort and 100 in the AdjBW cohort. The median dosing weight was significantly higher in the ABW group (95.9 vs 82.2 kg; p = 0.001). There was no statistical difference in percent of RASS measurements in goal range (61.5% vs 69.6%, p = 0.267) in patients that received dexmedetomidine dosed based on ABW versus AdjBW.Conclusion :Dosing dexmedetomidine using AdjBW in obese critically ill patients for ongoing ICU sedation resulted in no statistical difference in the percent of RASS measurements within goal when compared to ABW dosing. Further studies are warranted.
Urban Education, Ahead of Print. Belonging matters in early childhood. Despite its importance, the majoritarian conceptualization of belonging is seldom problematized. In the US, the politics of belonging draws racialized lines of inclusion and exclusion, (re)inscribing longstanding racialized systems of inequity and injustice. Through critical race and Latina feminist perspectives and methodologies, an immigrant mother and son of Color examined their lived experiences. Finding unveil the urgency of upending formal racialized notions of belonging—for example, citizenship, co naturalized with whiteness. Attending to the palpable consequences of ideological and relational borders that exclude and subjugate immigrants of Color, implications call for abolishing belonging as property and cultivating collective healing.
The family of metal halide (MH) nanocrystal materials is still vastly unexplored and unlocking their full potential is just at the beginning. The understanding and, therefore, the optimization of the properties of these nanoscale systems passes through a series of experimental characterization techniques that span compositional analysis, resolution of unknown (nano)crystal phases, determination of the nanocrystal facets, assessment of ligands bound to the surface, and analysis of the optical properties.
Owing to clinical success of immune checkpoint blockade, immunotherapy is becoming a cornerstone of modern oncology, and immuno oncology is at the forefront of basic cancer research. This commentary outlines future opportunities for immuno oncology modeling.
The leaf epidermis is a dynamic biomechanical shell that integrates growth across spatial scales to influence organ morphology. Pavement cells, the fundamental unit of this tissue, morph irreversibly into highly lobed cells that drive planar leaf expansion. Here, we define how tissue-scale cell wall tensile forces and the microtubule–cellulose synthase systems dictate the patterns of interdigitated growth in real time. A morphologically potent subset of cortical microtubules span the periclinal and anticlinal cell faces to pattern cellulose fibres that generate a patch of anisotropic wall. The subsequent local polarized growth is mechanically coupled to the adjacent cell via a pectin-rich middle lamella, and this drives lobe formation. Finite element pavement cell models revealed cell wall tensile stress as an upstream patterning element that links cell- and tissue-scale biomechanical parameters to interdigitated growth. Cell lobing in leaves is evolutionarily conserved, occurs in multiple cell types and is associated with important agronomic traits. Our general mechanistic models of lobe formation provide a foundation to analyse the cellular basis of leaf morphology and function.
In article number 2003968, Vincenzo Pecunia and co‐workers demonstrate the wide applicability of photoinduced current transient spectroscopy (PICTS) for the characterization of defect levels in lead‐free perovskite‐inspired materials. In PICTS, light induces a mechanism through which carriers are captured by the defect levels, as if in a metaphorical perovskite‐inspired billiard game. Due to its versatility, PICTS could catalyze the development of environmentally‐friendly perovskite‐inspired materials with benign defect properties for next‐generation photovoltaics.
The number of therapies for heart failure (HF) with reduced ejection fraction has nearly doubled in the past decade. In addition, new therapies for HF caused by hypertrophic and infiltrative disease are emerging rapidly. Indeed, we are on the verge of a new era in HF in which insights into the biology of myocardial disease can be matched to an understanding of the genetic predisposition in an individual patient to inform precision approaches to therapy. In this Review, we summarize the biology of HF, emphasizing the causal relationships between genetic contributors and traditional structure-based remodelling outcomes, and highlight the mechanisms of action of traditional and novel therapeutics. We discuss the latest advances in our understanding of both the Mendelian genetics of cardiomyopathy and the complex genetics of the clinical syndrome presenting as HF. In the phenotypic domain, we discuss applications of machine learning for the subcategorization of HF in ways that might inform rational prescribing of medications. We aim to bridge the gap between the biology of the failing heart, its diverse clinical presentations and the range of medications that we can now use to treat it. We present a roadmap for the future of precision medicine in HF.