Relative equilibria for the generalized rigid body

This paper gives necessary and sufficient conditions for the (n-dimensional) generalized free rigid body to be in a state of relative equilibrium. The conditions generalize those for the case of the three-dimensional free rigid body, namely that the body is in relative equilibrium if and only if its angular velocity and angular momentum align, that is, if the body rotates about one of its principal axes. For the n-dimensional rigid body in the Manakov formulation, these conditions have a similar interpretation. We use this result to state and prove a generalized Saari’s Conjecture (usually stated for the N-body problem) for the special case of the generalized rigid body

Relative Equilibria for the Generalized Rigid Body

This paper gives necessary and sufficient conditions for the (n-dimensional) generalized free rigid body to be in a state of relative equilibrium. The conditions generalize those for the case of the three-dimensional free rigid body, namely that the body is in relative equilibrium if and only if its angular velocity and angular momentum align, that is, if the body rotates about one of its principal axes. For the n-dimensional rigid body in the Manakov formulation, these conditions have a similar interpretation. We use this result to state and prove a generalized Saari’s Conjecture (usually stated for the N-body problem) for the special case of the generalized rigid body

Mrgprd Enhances Excitability in Specific Populations of Cutaneous Murine Polymodal Nociceptors

The Mas-related G protein-coupled receptor D (Mrgprd) is selectively expressed in nonpeptidergic nociceptors that innervate the outer layers of mammalian skin. The function of Mrgprd in nociceptive neurons and the physiologically relevant somatosensory stimuli that activate Mrgprd^-expressing (Mrgprd^+) neurons are currently unknown. To address these issues, we studied three Mrgprd knock-in mouse lines using an ex vivo somatosensory preparation to examine the role of the Mrgprd receptor and Mrgprd+ afferents in cutaneous somatosensation. In mouse hairy skin, Mrgprd, as marked by expression of green fluorescent protein reporters, was expressed predominantly in the population of nonpeptidergic, TRPV1-negative, C-polymodal nociceptors. In mice lacking Mrgprd, this population of nociceptors exhibited decreased sensitivity to cold, heat, and mechanical stimuli. Additionally, in vitro patch-clamp studies were performed on cultured dorsal root ganglion neurons from Mrgprd^(–/–) and Mrgprd^(+/–) mice. These studies revealed a higher rheobase in neurons from Mrgprd^(–/–) mice than from Mrgprd^(+/–) mice. Furthermore, the application of the Mrgprd ligand β-alanine significantly reduced the rheobase and increased the firing rate in neurons from Mrgprd^(+/–) mice but was without effect in neurons from Mrgprd^(–/–) mice. Our results demonstrate that Mrgprd influences the excitability of polymodal nonpeptidergic nociceptors to mechanical and thermal stimuli

Serial Cytoreductive Surgery and Survival Outcomes in Recurrent Adult-Type Ovarian Granulosa Cell Tumors

BACKGROUND: Few studies have evaluated the role of cytoreductive surgery in patients with recurrent adult granulosa cell tumors of the ovary. Despite a multitude of treatment modalities in the recurrent setting, the optimal management strategy is not known. Cytoreductive surgery offers an attractive option for disease confined to the abdomen/pelvis. However, few studies have evaluated the role of surgery compared with systemic therapy alone following the first recurrence and subsequent disease progressions. OBJECTIVE: This study aimed to determine the impact of secondary, tertiary, and quaternary cytoreductive surgery on survival outcomes in recurrent adult granulosa cell tumors of the ovary. STUDY DESIGN: This is a multicenter, retrospective cohort study evaluating patients with recurrent adult granulosa cell tumors of the ovary enrolled in the MD Anderson Rare Gynecologic Malignancy Registry from 1970 to 2022. Study inclusion criteria consisted of histology-proven recurrent disease, at least 1 documented recurrence, and treatment/treatment planning at the MD Anderson Cancer Center or Lyndon B. Johnson General Hospital. The primary exposure was cytoreductive surgery, and the outcomes of interest were progression-free survival and overall survival. Survival analyses were restricted to eligible patients with resectable disease without medical barriers to surgery at each progression episode. Demographic and clinicopathologic characteristics were summarized using descriptive statistics. Progression-free survival (after first, second, and third progression) and overall survival were estimated with methods of Kaplan and Meier, and were modeled via Cox proportional hazards regression. Multivariable analyses were performed for progression-free survival after first progression and overall survival. RESULTS: Among the 369 patients with adult granulosa cell tumors of the ovary in the registry, 149 patients met the study inclusion criteria. Secondary cytoreductive surgery was associated with a significant improvement in progression-free survival on univariable (hazard ratio, 0.37; 95% confidence interval, 0.17-0.81, P=.01) and multivariable analyses (hazard ratio, 0.42; 95% confidence interval, 0.19-0.92; P=.03). Those who underwent secondary cytoreductive surgery had a significantly improved median overall survival compared with those who did not undergo cytoreductive surgery (181.92 vs 61.56 months, respectively; P=.002). Overall survival benefit remained statistically significant on multivariable analysis (hazard ratio, 0.28; 95% confidence interval, 0.11-0.67; P=.004). Tertiary cytoreductive surgery was similarly associated with a significant improvement in progression-free survival (hazard ratio, 0.43; 95% confidence interval, 0.26-0.70; P=.001). Despite a similar trend, quaternary cytoreductive surgery was not associated with a significant improvement in progression-free survival (hazard ratio, 0.74; 95% confidence interval, 0.42-1.26; P=.27). CONCLUSION: Among those with resectable disease and no medical contraindications to surgery, cytoreductive surgery may have a beneficial impact on progression-free survival and overall survival in patients with recurrent adult granulosa cell tumors of the ovary

Clinical Outcomes of Leuprolide Acetate in the Treatment of Recurrent Ovarian Granulosa Cell Tumors

BACKGROUND: The optimal treatment of recurrent ovarian granulosa cell tumors is not known. Preclinical studies and small case series have suggested direct antitumor activity of gonadotropin-releasing hormone agonists in the treatment of this disease, but little is known about the efficacy and safety of this approach. OBJECTIVE: This study aimed to describe patterns of use and clinical outcomes of leuprolide acetate in a cohort of patients with recurrent granulosa cell tumors. STUDY DESIGN: This was a retrospective cohort study of patients enrolled in the Rare Gynecologic Malignancy Registry at a large cancer referral center and affiliated county hospital. Patients meeting inclusion criteria had a diagnosis of recurrent granulosa cell tumor and received either leuprolide acetate or traditional chemotherapy as cancer treatment. Outcomes were separately examined for leuprolide acetate used as adjuvant treatment, maintenance therapy, and the treatment of gross disease. Demographic and clinical data were summarized using descriptive statistics. Progression-free survival was calculated from the initiation of treatment to the date of disease progression or death, and compared between groups with the log-rank test. The 6-month clinical benefit rate was defined as the percentage of patients without disease progression 6 months after starting therapy. RESULTS: Sixty-two patients received a total of 78 leuprolide acetate-containing therapy courses, owing to 16 instances of retreatment. Of these 78 courses, 57 (73%) were for treatment of gross disease, 10 (13%) were adjuvant to tumor reductive surgery, and 11 (14%) were for maintenance therapy. Patients had received a median of 2 (interquartile range, 1-3) systemic therapy regimens before their first leuprolide acetate treatment. Tumor reductive surgery (100% [62/62]) and platinum-based chemotherapy (81% [50/62]) were common before first leuprolide acetate exposure. The median duration of leuprolide acetate therapy was 9.6 months (interquartile range, 4.8-16.5). Nearly half of the therapy courses were single-agent leuprolide acetate (49% [38/78]). Combination regimens most often included an aromatase inhibitor (23% [18/78]). Disease progression was the most common cause of discontinuation (77% [60/78]); only 1 patient (1%) discontinued leuprolide acetate because of adverse events. In the treatment of gross disease, the 6-month clinical benefit rate for first use of leuprolide acetate was 66% (95% confidence interval, 54-82). Median progression-free survival was not statistically different compared with that which followed chemotherapy (10.3 months [95% confidence interval, 8.0-16.0] vs 8.0 months [95% confidence interval, 5.0-15.3]; P=.3). CONCLUSION: In a large cohort of patients with recurrent granulosa cell tumors, the 6-month clinical benefit rate of first-time leuprolide acetate treatment of gross disease was 66% and progression-free survival was comparable to patients treated with chemotherapy. Leuprolide acetate regimens were heterogeneous, but significant toxicity was rare. These results support leuprolide acetate as safe and effective for the treatment of relapsed adult granulosa cell tumors in the second line and beyond

IHMCIF: An Extension of the PDBx/mmCIF Data Standard for Integrative Structure Determination Methods

IHMCIF (github.com/ihmwg/IHMCIF) is a data information framework that supports archiving and disseminating macromolecular structures determined by integrative or hybrid modeling (IHM), and making them Findable, Accessible, Interoperable, and Reusable (FAIR). IHMCIF is an extension of the Protein Data Bank Exchange/macromolecular Crystallographic Information Framework (PDBx/mmCIF) that serves as the framework for the Protein Data Bank (PDB) to archive experimentally determined atomic structures of biological macromolecules and their complexes with one another and small molecule ligands (e.g., enzyme cofactors and drugs). IHMCIF serves as the foundational data standard for the PDB-Dev prototype system, developed for archiving and disseminating integrative structures. It utilizes a flexible data representation to describe integrative structures that span multiple spatiotemporal scales and structural states with definitions for restraints from a variety of experimental methods contributing to integrative structural biology. The IHMCIF extension was created with the benefit of considerable community input and recommendations gathered by the Worldwide Protein Data Bank (wwPDB) Task Force for Integrative or Hybrid Methods (wwpdb.org/task/hybrid). Herein, we describe the development of IHMCIF to support evolving methodologies and ongoing advancements in integrative structural biology. Ultimately, IHMCIF will facilitate the unification of PDB-Dev data and tools with the PDB archive so that integrative structures can be archived and disseminated through PDB

Parallels, prescience and the past: analogical reasoning and contemporary international politics

Analogical reasoning has held a perpetual appeal to policymakers who have often drafted in historical metaphor as a mode of informing decision-making. However, this article contends that since the beginning of the ‘War on Terror’ we have arguably seen the rise of a more potent form of analogy, namely ones that are selected because they fulfil an ideological function. Analogical reasoning as a tool of rational decision-making has increasingly become replaced by analogical reasoning as a tool of trenchant ideologically-informed policy justification. This article addresses three key areas which map out the importance of analogical reasoning to an understanding of developments in contemporary international politics: the relationship between history and politics, in intellectual and policy terms; a critical assessment of the appeal that analogical reasoning holds for policymakers; and the development of a rationale for a more effective use of history in international public policymaking

Federating structural models and data:Outcomes from a workshop on archiving integrative structures

Structures of biomolecular systems are increasingly computed by integrative modeling. In this approach, a structural model is constructed by combining information from multiple sources, including varied experimental methods and prior models. In 2019, a Workshop was held as a Biophysical Society Satellite Meeting to assess progress and discuss further requirements for archiving integrative structures. The primary goal of the Workshop was to build consensus for addressing the challenges involved in creating common data standards, building methods for federated data exchange, and developing mechanisms for validating integrative structures. The summary of the Workshop and the recommendations that emerged are presented here

Identification of an Intracellular Site of Prion Conversion

Prion diseases are fatal, neurodegenerative disorders in humans and animals and are characterized by the accumulation of an abnormally folded isoform of the cellular prion protein (PrPC), denoted PrPSc, which represents the major component of infectious scrapie prions. Characterization of the mechanism of conversion of PrPC into PrPSc and identification of the intracellular site where it occurs are among the most important questions in prion biology. Despite numerous efforts, both of these questions remain unsolved. We have quantitatively analyzed the distribution of PrPC and PrPSc and measured PrPSc levels in different infected neuronal cell lines in which protein trafficking has been selectively impaired. Our data exclude roles for both early and late endosomes and identify the endosomal recycling compartment as the likely site of prion conversion. These findings represent a fundamental step towards understanding the cellular mechanism of prion conversion and will allow the development of new therapeutic approaches for prion diseases

Training attention control of very preterm infants: protocol for a feasibility study of the Attention Control Training (ACT)

Background Children born preterm may display cognitive, learning, and behaviour difficulties as they grow up. In particular, very premature birth (gestation age between 28 and less than 32 weeks) may put infants at increased risk of intellectual deficits and attention deficit disorder. Evidence suggests that the basis of these problems may lie in difficulties in the development of executive functions. One of the earliest executive functions to emerge around 1 year of age is the ability to control attention. An eye-tracking-based cognitive training programme to support this emerging ability, the Attention Control Training (ACT), has been developed and tested with typically developing infants. The aim of this study is to investigate the feasibility of using the ACT with healthy very preterm (VP) infants when they are 12 months of age (corrected age). The ACT has the potential to address the need for supporting emerging cognitive abilities of VP infants with an early intervention, which may capitalise on infants’ neural plasticity. Methods/design The feasibility study is designed to investigate whether it is possible to recruit and retain VP infants and their families in a randomised trial that compares attention and social attention of trained infants against those that are exposed to a control procedure. Feasibility issues include the referral/recruitment pathway, attendance, and engagement with testing and training sessions, completion of tasks, retention in the study, acceptability of outcome measures, quality of data collected (particularly, eye-tracking data). The results of the study will inform the development of a larger randomised trial. Discussion Several lines of evidence emphasise the need to support emerging cognitive and learning abilities of preterm infants using early interventions. However, early interventions with preterm infants, and particularly very preterm ones, face difficulties in recruiting and retaining participants. These problems are also augmented by the health vulnerability of this population. This feasibility study will provide the basis for informing the implementation of an early cognitive intervention for very preterm infants. Trial registration Registered Registration ID: NCT03896490. Retrospectively registered at Clinical Trials Protocol Registration and Results System (clinicaltrials.gov)