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Transgender rights discussions often turn on the distinction between “gender identity” and “sex assigned at birth.” Gender identity is a person’s own internal sense of whether they are a man, a woman, or nonbinary. “Sex assigned at birth” means the male or female designation that doctors ascribe to infants based on genitalia and is marked on their birth records. Sex assigned at birth is intended to displace the concept of “biological sex.” This Article provides an account of the origins of the terms “biological sex” and “sex assigned at birth” and assesses the potential of the shift to sex assigned at birth for transgender rights arguments. The debate is not one over mere nomenclature. This Article’s examination reveals that the term “biological sex” rose to prominence to lend a veneer of scientific support to projects denying the validity of transgender identities and that the unquestioned use of that concept continues to underwrite exclusion. By referring instead to sex assigned at birth, transgender rights advocates convey that “biological sex” is not simple, static, or binary and that gender identity also has biological aspects. Furthermore, the phrase “assigned at birth” invokes philosophical arguments against assigning particular social roles to individuals at birth. It taps into the moral intuition that a person’s genitalia and health data are private matters. This Article argues that sex assigned at birth is an important concept that clarifies the stakes of disputes over transgender rights. But it cautions that this conceptual shift is not sufficient to secure victories in transgender rights litigation. Ultimately, definitional debates about sex and gender cannot resolve the moral and practical questions at the heart of contemporary controversies over transgender rights. Recent legal victories on transgender rights issues have done more than debate the meanings of sex and gender: They have addressed practical objections to transgender inclusion, cultivated empathy for plaintiffs, and staked claims in the registers of equality, autonomy, and dignity.

Nonbinary gender identities have quickly gone from obscurity to prominence in American public life, with growing acceptance of gender-neutral pronouns, such as “they, them, and theirs,” and recognition of a third-gender category by U.S. states including California, Colorado, Minnesota, New Jersey, Oregon, and Washington. People with nonbinary gender identities do not exclusively identify as men or women. Feminist legal reformers have long argued that discrimination on the basis of gender nonconformity — in other words, discrimination against men perceived as feminine or women perceived as masculine — is a harmful type of sex discrimination that the law should redress. But the idea of nonbinary gender as an identity itself appears only at the margins of U.S. legal scholarship. Many of the cases recognizing transgender rights involve plaintiffs who identify as men or women, rather than plaintiffs who seek to reject, permute, or transcend those categories. The increased visibility of a nonbinary minority creates challenges for other rights movements, while also opening new avenues for feminist and LGBT advocacy. This Article asks what the law would look like if it took nonbinary gender seriously. It assesses the legal interests in binary gender regulation in areas including law enforcement, employment, education, housing, and health care, and concludes these interests are not reasons to reject nonbinary gender rights. It argues that the law can recognize nonbinary gender identities, or eliminate unnecessary legal sex classifications, using familiar civil rights concepts.

Cyclin-dependent kinases (CDKs) contribute to the cancer hallmarks of uncontrolled proliferation and increased survival. As a result, over the last two decades substantial efforts have been directed towards identification and development of pharmaceutical CDK inhibitors. Insights into the biological consequences of CDK inhibition in specific tumor types have led to the successful development of CDK4/6 inhibitors as treatments for certain types of breast cancer. More recently, a new generation of pharmaceutical inhibitors of CDK enzymes that regulate the transcription of key oncogenic and pro-survival proteins, including CDK9, have entered clinical development. Here, we provide the first disclosure of the chemical structure of fadraciclib (CYC065), a CDK inhibitor and clinical candidate designed by further optimization from the aminopurine scaffold of seliciclib. We describe its synthesis and mechanistic characterization. Fadraciclib exhibits improved potency and selectivity for CDK2 and CDK9 compared to seliciclib, and also displays high selectivity across the kinome. We show that the mechanism of action of fadraciclib is consistent with potent inhibition of CDK9-mediated transcription, decreasing levels of RNA polymerase II C-terminal domain serine 2 phosphorylation, the pro-survival protein Myeloid Cell Leukemia 1 (MCL1) and MYC oncoprotein, and inducing rapid apoptosis in cancer cells. This cellular potency and mechanism of action translate to promising anti-cancer activity in human leukemia mouse xenograft models. Studies of leukemia cell line sensitivity identify mixed lineage leukemia ( MLL ) gene status and the level of B-cell lymphoma 2 (BCL2) family proteins as potential markers for selection of patients with greater sensitivity to fadraciclib. We show that the combination of fadraciclib with BCL2 inhibitors, including venetoclax, is synergistic in leukemic cell models, as predicted from simultaneous inhibition of MCL1 and BCL2 pro-survival pathways. Fadraciclib preclinical pharmacology data support its therapeutic potential in CDK9- or CDK2-dependent cancers and as a rational combination with BCL2 inhibitors in hematological malignancies. Fadraciclib is currently in Phase 1 clinical studies in patients with advanced solid tumors ( NCT02552953 ) and also in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) ( NCT03739554 ) and relapsed refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) ( NCT04017546 ).

Despite making up one of the most ecologically diverse groups of living birds, comprising soaring, diving and giant flightless taxa, the evolutionary relationships and ecological evolution of Anseriformes (waterfowl) remain unresolved. Although Anseriformes have a comparatively rich, global Cretaceous and Paleogene fossil record, morphological datasets for this group that include extinct taxa report conflicting relationships for all known extinct taxa. Correct placement of extinct taxa is necessary to understand whether ancestral anseriform feeding ecology was more terrestrial or one of a set of diverse aquatic ecologies and to better understand avian evolution around the K-T boundary. Here, we present a new morphological dataset for Anseriformes that includes more extant and extinct taxa than any previous anseriform-focused dataset and describe a new anseriform species from the early Eocene Green River Formation of North America. The new taxon has a mediolaterally narrow bill which is rarely found in previously described anseriform fossils. The matrix created to assess the placement of this taxon comprises 41 taxa and 719 discrete morphological characters describing skeletal morphology, musculature, syringeal morphology, ecology, and behavior. We additionally combine the morphological dataset with published sequences using Bayesian methods and perform ancestral state reconstruction for select morphological, ecological and behavioral characters. We recover the new Eocene taxon as the sister taxon to (Anseranatidae+Anatidae) across all analyses, and find that the new taxon represents a novel ecology within known Anseriformes and the Green River taxa. Results provide insight into avian evolution during and following the K-Pg mass extinction and indicate that Anseriformes were likely ancestrally aquatic herbivores with rhamphothecal lamellae..

Flow between axially rotating concentric cylinders is well known to exhibit rich dynamics. Hence, Taylor instabilities have been studied, both experimentally and theoretically, for many years. Although usually studied in the abstract, such geometries arise in a range of practical situations including drilling, when a drilling fluid flow enters a well via a pipe that is the centre body and returns via the annulus between the pipe and the borehole wall. In drilling, the centre body rotates and the annular flow contains rock cuttings. Here, we report the development of an Eulerian-Eulerian solver, based on OpenFOAM, that solves for this cuttings transport problem in the presence of both gravity and Taylor vortices. To check the reliability of the solver, we conduct a set of experiments spanning a wide range of complex flow regimes. We show that the model successfully predicts, in all regimes, the observed complex redistribution of particulates. However, for suspension flows under viscously dominated conditions, high particle concentrations and in rectilinear flow, particle pressure and normal stress differences are sufficient to capture particle migration. Results show that in more complex flows exemplified by the Taylor–Couette flow studied here, more realistic predictions of non-Brownian particle migration require inclusion of forces arising through the relative velocity of the two phases including lift forces originating both from inertia and particle rotation.

Abstract Infertility affects one in six of the population and increasingly couples require treatment with assisted reproductive techniques. In vitro fertilization (IVF) treatment is most commonly conducted using exogenous FSH to induce follicular growth and human chorionic gonadotropin (hCG) to induce final oocyte maturation. However, hCG may cause the potentially life-threatening iatrogenic complication \"ovarian hyperstimulation syndrome\" (OHSS), which can cause considerable morbidity and, rarely, even mortality in otherwise healthy women. The use of GnRH agonists (GnRHas) has been pioneered during the last two decades to provide a safer option to induce final oocyte maturation. More recently, the neuropeptide kisspeptin, a hypothalamic regulator of GnRH release, has been investigated as a novel inductor of oocyte maturation. The hormonal stimulus used to induce oocyte maturation has a major impact on the success (retrieval of oocytes and chance of implantation) and safety (risk of OHSS) of IVF treatment. This review aims to appraise experimental and clinical data of hormonal approaches used to induce final oocyte maturation by hCG, GnRHa, both GnRHa and hCG administered in combination, recombinant LH, or kisspeptin. We also examine evidence for the timing of administration of the inductor of final oocyte maturation in relationship to parameters of follicular growth and the subsequent interval to oocyte retrieval. In summary, we review data on the efficacy and safety of the major hormonal approaches used to induce final oocyte maturation in clinical practice, as well as some novel approaches that may offer fresh alternatives in future.

The discovery and development of small molecule cancer drugs has been revolutionised over the last decade. Most notably, we have moved from a one-size-fits-all approach that emphasized cytotoxic chemotherapy to a personalised medicine strategy that focuses on the discovery and development of molecularly targeted drugs that exploit the particular genetic addictions, dependencies and vulnerabilities of cancer cells. These exploitable characteristics are increasingly being revealed by our expanding understanding of the abnormal biology and genetics of cancer cells, accelerated by cancer genome sequencing and other high-throughput genome-wide campaigns, including functional screens using RNA interference. In this review we provide an overview of contemporary approaches to the discovery of small molecule cancer drugs, highlighting successes, current challenges and future opportunities. We focus in particular on four key steps: Target validation and selection; chemical hit and lead generation; lead optimization to identify a clinical drug candidate; and finally hypothesis-driven, biomarker-led clinical trials. Although all of these steps are critical, we view target validation and selection and the conduct of biology-directed clinical trials as especially important areas upon which to focus to speed progress from gene to drug and to reduce the unacceptably high attrition rate during clinical development. Other challenges include expanding the envelope of druggability for less tractable targets, understanding and overcoming drug resistance, and designing intelligent and effective drug combinations. We discuss not only scientific and technical challenges, but also the assessment and mitigation of risks as well as organizational, cultural and funding problems for cancer drug discovery and development, together with solutions to overcome the ‘Valley of Death’ between basic research and approved medicines. We envisage a future in which addressing these challenges will enhance our rapid progress towards truly personalised medicine for cancer patients. ► Here we review small molecule cancer drug discovery and development. ► We focus on Target selection, hit identification, lead optimization and clinical trials. ► A particular emphasis of this article is personalized medicine.

Single-cell transcriptomics can profile thousands of cells in a single experiment and identify novel cell types, states and dynamics in a wide variety of tissues and organisms. Standard experimental protocols and analysis workflows have been developed to create single-cell transcriptomic maps from tissues. This tutorial focuses on how to interpret these data to identify cell types, states and other biologically relevant patterns with the objective of creating an annotated map of cells. We recommend a three-step workflow including automatic cell annotation (wherever possible), manual cell annotation and verification. Frequently encountered challenges are discussed, as well as strategies to address them. Guiding principles and specific recommendations for software tools and resources that can be used for each step are covered, and an R notebook is included to help run the recommended workflow. Basic familiarity with computer software is assumed, and basic knowledge of programming (e.g., in the R language) is recommended. This tutorial provides guidelines for interpreting single-cell transcriptomic maps to identify cell types, states and other biologically relevant patterns.

Critics of the Supreme Court's equal protection jurisprudence despair that the Court conceives of discrimination as the mere classification of individuals on forbidden grounds, such as race and sex, rather than systemic patterns of subordination. On the Court's anticlassification theory, affirmative action, which relies on overt racial or gender classifications, is generally forbidden. Anticlassification rules are insensitive to context: a classification is a classification, no matter how well-intentioned it might be, no matter what effects it might have, and no matter if it treats members of various groups in ways that are substantively equal. Whether a classification might be justified due to its purposes, effects, or substance is a separate inquiry demanding careful judicial scrutiny. Such context-insensitive anticlassification rules could, in principle, extend to individuals who are members of groups often regarded with hostility and suspicion, such as transgender people. Indeed, this is how most trial courts have approached recent laws that classify individuals based on sex to exclude transgender people—concluding that those laws trigger heightened scrutiny and asking whether they serve important governmental interests. However, in a series of recent sex discrimination cases involving transgender plaintiffs, appellate courts have refused to take anticlassification rules seriously. For these judges, a classification is not a classification if it appears, by their own dim normative lights, to treat the sexes equally. These courts give a free pass to sex classifications that target transgender people, declining to ask what important interests these laws might serve. This Article argues that all sex classifications, like all race-based ones, ought to trigger heightened constitutional scrutiny. It draws support from the principles undergirding anticlassification rules announced by the Roberts Court, most recently in its university affirmative-action decisions. Rather than being empty formalism, as critics contend, anticlassification theory is based in principles related to individual autonomy. These principles provide no basis for defining what counts as a classification differently in the context of sex as opposed to race, nor do they support exceptions to equal protection for transgender people.