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Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development., (© 2024. The Author(s).)

Motivation: AliGater is an open-source framework to accelerate the development of bioinformatic pipelines for the analysis of large-scale, high-dimensional flow cytometry data. AliGater provides a Python package for automatic feature extraction workflows, as well as building blocks to construct analysis pipelines., Results: We illustrate the use of AliGater in a high-resolution flow cytometry-based genome-wide association study on 46 immune cell populations in 14 288 individuals., Availability and Implementation: Source code and documentation at https://github.com/LudvigEk/aligater and https://aligater.readthedocs.io., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press.)

In this paper, we construct the metric tensor and volume for the manifold of purifications associated with an arbitrary reduced density operator ρS. We also define a quantum coarse-graining (CG) to study the volume where macrostates are the manifolds of purifications, which we call surfaces of ignorance (SOI), and microstates are the purifications of ρS. In this context, the volume functions as a multiplicity of the macrostates that quantifies the amount of information missing from ρS. Using examples where the SOI are generated using representations of SU(2), SO(3), and SO(N), we show two features of the CG: (1) A system beginning in an atypical macrostate of smaller volume evolves to macrostates of greater volume until it reaches the equilibrium macrostate in a process in which the system and environment become strictly more entangled, and (2) the equilibrium macrostate takes up the vast majority of the coarse-grained space especially as the dimension of the total system becomes large. Here, the equilibrium macrostate corresponds to a maximum entanglement between the system and the environment. To demonstrate feature (1) for the examples considered, we show that the volume behaves like the von Neumann entropy in that it is zero for pure states, maximal for maximally mixed states, and is a concave function with respect to the purity of ρS. These two features are essential to typicality arguments regarding thermalization and Boltzmann's original CG.

The effect of the Adapted-Coping with Stress (A-CWS) intervention on social support coping was examined, using a randomized controlled trial design. The participants were 410 ninth-grade students (ages 14 to 16 years and mostly African American) living in low-resourced neighborhoods. Participants were randomly assigned 1:1 to either the A-CWS intervention or a standard care control condition. All participants were assessed at their schools before implementation of the intervention, at intervention completion, and again at 6- and 12-month post-intervention. Engagement in social support coping was examined in both intention-to-treat and treatment-as-received samples (i.e., intervention participants who attended at least 12 A-CWS treatment sessions and participants in the standard care control condition), using latent growth models. In intention-to-treat analyses, no significant treatment effects were identified. In treatment-as-received analyses, results revealed a significant association between social support coping and treatment condition; levels of social support coping decreased over time in the control condition, but they remained relatively stable in the treatment condition. The results indicate adequate intervention adherence and efficacy of the A-CWS to sustain social support coping within a sample of youth at high risk for stress exposure and associated disorders.Clinical Trial Registration: clinicaltrials.gov identifier: NCT0395445., (© 2022. Society for Prevention Research.)

Stem cell transplantation is a cornerstone in the treatment of blood malignancies. The most common method to harvest stem cells for transplantation is by leukapheresis, requiring mobilization of CD34+ hematopoietic stem and progenitor cells (HSPCs) from the bone marrow into the blood. Identifying the genetic factors that control blood CD34+ cell levels could reveal new drug targets for HSPC mobilization. Here we report the first large-scale, genome-wide association study on blood CD34+ cell levels. Across 13 167 individuals, we identify 9 significant and 2 suggestive associations, accounted for by 8 loci (PPM1H, CXCR4, ENO1-RERE, ITGA9, ARHGAP45, CEBPA, TERT, and MYC). Notably, 4 of the identified associations map to CXCR4, showing that bona fide regulators of blood CD34+ cell levels can be identified through genetic variation. Further, the most significant association maps to PPM1H, encoding a serine/threonine phosphatase never previously implicated in HSPC biology. PPM1H is expressed in HSPCs, and the allele that confers higher blood CD34+ cell levels downregulates PPM1H. Through functional fine-mapping, we find that this downregulation is caused by the variant rs772557-A, which abrogates an MYB transcription factor-binding site in PPM1H intron 1 that is active in specific HSPC subpopulations, including hematopoietic stem cells, and interacts with the promoter by chromatin looping. Furthermore, PPM1H knockdown increases the proportion of CD34+ and CD34+90+ cells in cord blood assays. Our results provide the first large-scale analysis of the genetic architecture of blood CD34+ cell levels and warrant further investigation of PPM1H as a potential inhibition target for stem cell mobilization., (© 2022 by The American Society of Hematology.)

We present an information geometric characterization of quantum driving schemes specified by su(2;C) time-dependent Hamiltonians in terms of both complexity and efficiency concepts. Specifically, starting from pure output quantum states describing the evolution of a spin-1/2 particle in an external time-dependent magnetic field, we consider the probability paths emerging from the parametrized squared probability amplitudes of quantum origin. The information manifold of such paths is equipped with a Riemannian metrization specified by the Fisher information evaluated along the parametrized squared probability amplitudes. By employing a minimum action principle, the optimum path connecting initial and final states on the manifold in finite time is the geodesic path between the two states. In particular, the total entropy production that occurs during the transfer is minimized along these optimum paths. For each optimum path that emerges from the given quantum driving scheme, we evaluate the so-called information geometric complexity (IGC) and our newly proposed measure of entropic efficiency constructed in terms of the constant entropy production rates that specify the entropy minimizing paths being compared. From our analytical estimates of complexity and efficiency, we provide a relative ranking among the driving schemes being investigated. Moreover, we determine that the efficiency and the temporal rate of change of the IGC are monotonic decreasing and increasing functions, respectively, of the constant entropic speed along these optimum paths. Then, after discussing the connection between thermodynamic length and IGC in the physical scenarios being analyzed, we briefly examine the link between IGC and entropy production rate. Finally, we conclude by commenting on the fact that an higher entropic speed in quantum transfer processes seems to necessarily go along with a lower entropic efficiency together with a higher information geometric complexity.

Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy., (© 2022. The Author(s).)

Child trafficking is one of the most egregious violations of children's rights and well-being. In 2014, the Global Alliance for Behavioral Health and Social Justice formed a task force to focus on the issue. After completing two comprehensive reviews and consultations with experts in the field, the task force identified the need for a coherent framework, which conceptualized the primary prevention of child trafficking, which includes children vulnerable to being trafficked and becoming traffickers. This article describes the process undertaken to develop the primary prevention framework, an innovative, aspirational plan for communities to be absent of trafficking. It describes the framework in detail, including the theories that underlie it and the principles that guide it. The framework's flexibility is evident in its application to such worldwide challenges as racism, inequities, and a pandemic. Although the full consequences of the impact of the COVID-19 pandemic on children are not yet known, this article describes certain trends, which have been identified and discusses critical lessons for applying a dynamic framework, as global disruptors will continue. The article ends with examples of how the framework could be implemented by all stakeholders in the community, to address the primary prevention of child trafficking in both the physical and the virtual world. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Is the oncogene MYC upregulated or hyperactive? In the majority of human cancers, finding agents that target c-MYC has proved difficult. Here we report specific bacterial effector molecules that inhibit cellular MYC (c-MYC) in human cells. We show that uropathogenic Escherichia coli (UPEC) degrade the c-MYC protein and attenuate MYC expression in both human cells and animal tissues. c-MYC protein was rapidly degraded by both cell-free bacterial lysates and the purified bacterial protease Lon. In mice, intravesical or peroral delivery of Lon protease delayed tumor progression and increased survival in MYC-dependent bladder and colon cancer models, respectively. These results suggest that bacteria have evolved strategies to control c-MYC tissue levels in the host and that the Lon protease shows promise for therapeutic targeting of c-MYC in cancer.

Attaining reliable gradient profiles is of utmost relevance for many physical systems. In many situations, the estimation of the gradient is inaccurate due to noise. It is common practice to first estimate the underlying system and then compute the gradient profile by taking the subsequent analytic derivative of the estimated system. The underlying system is often estimated by fitting or smoothing the data using other techniques. Taking the subsequent analytic derivative of an estimated function can be ill-posed. This becomes worse as the noise in the system increases. As a result, the uncertainty generated in the gradient estimate increases. In this paper, a theoretical framework for a method to estimate the gradient profile of discrete noisy data is presented. The method was developed within a Bayesian framework. Comprehensive numerical experiments were conducted on synthetic data at different levels of noise. The accuracy of the proposed method was quantified. Our findings suggest that the proposed gradient profile estimation method outperforms the state-of-the-art methods.

Multiple myeloma (MM) is caused by the uncontrolled, clonal expansion of plasma cells. While there is epidemiological evidence for inherited susceptibility, the molecular basis remains incompletely understood. We report a genome-wide association study totalling 5,320 cases and 422,289 controls from four Nordic populations, and find a novel MM risk variant at SOHLH2 at 13q13.3 (risk allele frequency = 3.5%; odds ratio = 1.38; P = 2.2 × 10 -14 ). This gene encodes a transcription factor involved in gametogenesis that is normally only weakly expressed in plasma cells. The association is represented by 14 variants in linkage disequilibrium. Among these, rs75712673 maps to a genomic region with open chromatin in plasma cells, and upregulates SOHLH2 in this cell type. Moreover, rs75712673 influences transcriptional activity in luciferase assays, and shows a chromatin looping interaction with the SOHLH2 promoter. Our work provides novel insight into MM susceptibility.

We present an information geometric analysis of entropic speeds and entropy production rates in geodesic evolution on manifolds of parametrized quantum states. These pure states emerge as outputs of suitable su(2;C) time-dependent Hamiltonian operators used to describe distinct types of analog quantum search schemes. The Riemannian metrization on the manifold is specified by the Fisher information evaluated along the parametrized squared probability amplitudes obtained from analysis of the temporal quantum mechanical evolution of a spin-1/2 particle in an external time-dependent magnetic field that specifies the su(2;C) Hamiltonian model. We employ a minimum action method to transfer a quantum system from an initial state to a final state on the manifold in a finite temporal interval. Furthermore, we demonstrate that the minimizing (optimum) path is the shortest (geodesic) path between the two states and, in particular, minimizes also the total entropy production that occurs during the transfer. Finally, by evaluating the entropic speed and the total entropy production along the optimum transfer paths in a number of physical scenarios of interest in analog quantum search problems, we show in a clear quantitative manner that to a faster transfer there corresponds necessarily a higher entropy production rate. Thus we conclude that lower entropic efficiency values appear to accompany higher entropic speed values in quantum transfer processes.

The nervous system is engaged by infection, indirectly through inflammatory cascades or directly, by bacterial attack on nerve cells. Here we identify a neuro-epithelial activation loop that participates in the control of mucosal inflammation and pain in acute cystitis. We show that infection activates Neurokinin-1 receptor (NK1R) and Substance P (SP) expression in nerve cells and bladder epithelial cells in vitro and in vivo in the urinary bladder mucosa. Specific innate immune response genes regulated this mucosal response, and single gene deletions resulted either in protection (Tlr4 -/- and Il1b -/- mice) or in accentuated bladder pathology (Asc -/- and Nlrp3 -/- mice), compared to controls. NK1R/SP expression was lower in Tlr4 -/- and Il1b -/- mice than in C56BL/6WT controls but in Asc -/- and Nlrp3 -/- mice, NK1R over-activation accompanied the exaggerated disease phenotype, due, in part to transcriptional de-repression of Tacr1. Pharmacologic NK1R inhibitors attenuated acute cystitis in susceptible mice, supporting a role in disease pathogenesis. Clinical relevance was suggested by elevated urine SP levels in patients with acute cystitis, compared to patients with asymptomatic bacteriuria identifying NK1R/SP as potential therapeutic targets. We propose that NK1R and SP influence the severity of acute cystitis through a neuro-epithelial activation loop that controls pain and mucosal inflammation.

The relevance of the concept of Fisher information is increasing in both statistical physics and quantum computing. From a statistical mechanical standpoint, the application of Fisher information in the kinetic theory of gases is characterized by its decrease along the solutions of the Boltzmann equation for Maxwellian molecules in the two-dimensional case. From a quantum mechanical standpoint, the output state in Grover's quantum search algorithm follows a geodesic path obtained from the Fubini-Study metric on the manifold of Hilbert-space rays. Additionally, Grover's algorithm is specified by constant Fisher information. In this paper, we present an information geometric characterization of the oscillatory or monotonic behavior of statistically parametrized squared probability amplitudes originating from special functional forms of the Fisher information function: constant, exponential decay, and power-law decay. Furthermore, for each case, we compute both the computational speed and the availability loss of the corresponding physical processes by exploiting a convenient Riemannian geometrization of useful thermodynamical concepts. Finally, we briefly comment on the possibility of using the proposed methods of information geometry to help identify a suitable trade-off between speed and thermodynamic efficiency in quantum search algorithms.