Despite the initial efficacy of androgen deprivation in prostate cancer, virtually all patients progress to castration-resistant prostate cancer (CRPC). Androgen receptor (AR) signaling is critically ...required for CRPC. A new generation of medications targeting AR, such as abiraterone and enzalutamide, has improved survival of metastatic CRPC (mCRPC) patients. However, a significant proportion of patients presents with primary resistance to these agents, and in the remainder, secondary resistance will invariably develop, which makes mCRPC the lethal form of the disease. Mechanisms underlying progression to mCRPC and treatment resistance are extremely complex. AR-dependent resistance mechanisms include
amplification,
point mutations, expression of constitutively active
splice variants, and altered intratumoral androgen biosynthesis. AR-independent resistance mechanisms include glucocorticoid receptor activation, immune-mediated resistance, and neuroendocrine differentiation. The development of novel agents, such as seviteronel, apalutamide, and EPI-001/EPI-506, as well as the identification and validation of novel predictive biomarkers of resistance, may lead to improved therapeutics for mCRPC patients.
Water content and the internal evolution of terrestrial planets and icy bodies are closely linked. The distribution of water in planetary systems is controlled by the temperature structure in the ...protoplanetary disk and dynamics and migration of planetesimals and planetary embryos. This results in the formation of planetesimals and planetary embryos with a great variety of compositions, water contents and degrees of oxidation. The internal evolution and especially the formation time of planetesimals relative to the timescale of radiogenic heating by short-lived
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Al decay may govern the amount of hydrous silicates and leftover rock–ice mixtures available in the late stages of their evolution. In turn, water content may affect the early internal evolution of the planetesimals and in particular metal-silicate separation processes. Moreover, water content may contribute to an increase of oxygen fugacity and thus affect the concentrations of siderophile elements within the silicate reservoirs of Solar System objects. Finally, the water content strongly influences the differentiation rate of the icy moons, controls their internal evolution and governs the alteration processes occurring in their deep interiors.
There is ample pathological and biological evidence for endo-lysosomal dysfunction in Alzheimer's disease (AD) and emerging genetic studies repeatedly implicate endo-lysosomal genes as associated ...with increased AD risk. The endo-lysosomal network (ELN) is essential for all cell types of the central nervous system (CNS), yet each unique cell type utilizes cellular trafficking differently (see Fig. 1). Challenges ahead involve defining the role of AD associated genes in the functionality of the endo-lysosomal network (ELN) and understanding how this impacts the cellular dysfunction that occurs in AD. This is critical to the development of new therapeutics that will impact, and potentially reverse, early disease phenotypes. Here we review some early evidence of ELN dysfunction in AD pathogenesis and discuss the role of selected AD-associated risk genes in this pathway. In particular, we review genes that have been replicated in multiple genome-wide association studies(Andrews et al., 2020; Jansen et al., 2019; Kunkle et al., 2019; Lambert et al., 2013; Marioni et al., 2018) and reviewed in(Andrews et al., 2020) that have defined roles in the endo-lysosomal network. These genes include SORL1, an AD risk gene harboring both rare and common variants associated with AD risk and a role in trafficking cargo, including APP, through the ELN; BIN1, a regulator of clathrin-mediated endocytosis whose expression correlates with Tau pathology; CD2AP, an AD risk gene with roles in endosome morphology and recycling; PICALM, a clathrin-binding protein that mediates trafficking between the trans-Golgi network and endosomes; and Ephrin Receptors, a family of receptor tyrosine kinases with AD associations and interactions with other AD risk genes. Finally, we will discuss how human cellular models can elucidate cell-type specific differences in ELN dysfunction in AD and aid in therapeutic development.
SORL1/SORLA is a sorting receptor involved in retromer-related endosomal traffic and an Alzheimer’s disease (AD) risk gene. Using CRISPR-Cas9, we deplete SORL1 in hiPSCs to ask if loss of SORL1 ...contributes to AD pathogenesis by endosome dysfunction. SORL1-deficient hiPSC neurons show early endosome enlargement, a hallmark cytopathology of AD. There is no effect of SORL1 depletion on endosome size in hiPSC microglia, suggesting a selective effect on neuronal endosomal trafficking. We validate defects in neuronal endosomal traffic by showing altered localization of amyloid precursor protein (APP) in early endosomes, a site of APP cleavage by the β-secretase (BACE). Inhibition of BACE does not rescue endosome enlargement in SORL1-deficient neurons, suggesting that this phenotype is independent of amyloidogenic APP processing. Our data, together with recent findings, underscore how sporadic AD pathways regulating endosomal trafficking and autosomal-dominant AD pathways regulating APP cleavage independently converge on the defining cytopathology of AD.
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•Depletion of SORL1, an AD risk gene, in hiPSCs to model late-onset AD•Loss of SORL1 leads to early endosome enlargement in neurons but not microglia•Endosome in enlargement is independent of amyloidogenic APP processing•Loss of SORL1 leads to altered trafficking of APP
Enlarged endosomes are an early cytopathology of Alzheimer’s disease (AD). Knupp et al. deplete the AD risk gene SORL1, a sorting receptor, in hiPSCs and report endosome enlargement in differentiated neurons but not microglia. Endosome enlargement is not dependent on amyloidogenic processing of APP but affects its trafficking within neurons.
Standard approaches for identifying task-completion strategies, such as precrastination and procrastination, reduce behavior to single markers that oversimplify the process of task completion. To ...illustrate this point, we consider three task-completion strategies and introduce a new method to identify their use. This approach was tested using an archival data set (N = 8,655) of the available electronic records of research participation at Kansas State University. The approach outperformed standard diagnostic approaches and yielded an interesting finding: Several strategies were associated with negative outcomes. Specifically, both procrastinators and precrastinators struggled to finish tasks on time. Together, these findings underscore the importance of using holistic approaches to determine the relationship among task characteristics, individual differences, and task completion.
Zika virus (ZIKV) is a mosquito-borne flavivirus responsible for thousands of cases of severe fetal malformations and neurological disease since its introduction to Brazil in 2013. Antibodies to ...flaviviruses can be protective, resulting in lifelong immunity to reinfection by homologous virus. However, cross-reactive antibodies can complicate flavivirus diagnostics and promote more severe disease, as noted after serial dengue virus (DENV) infections. The endemic circulation of DENV in South America and elsewhere raises concerns that preexisting flavivirus immunity may modulate ZIKV disease and transmission potential. Here, we report on the ability of human monoclonal antibodies and immune sera derived from dengue patients to neutralize contemporary epidemic ZIKV strains. We demonstrate that a class of human monoclonal antibodies isolated from DENV patients neutralizes ZIKV in cell culture and is protective in a lethal murine model. We also tested a large panel of convalescent-phase immune sera from humans exposed to primary and repeat DENV infection. Although ZIKV is most closely related to DENV compared to other human-pathogenic flaviviruses, most DENV immune sera (73%) failed to neutralize ZIKV, while others had low (50% effective concentration EC50, <1:100 serum dilution; 18%) or moderate to high (EC50, >1:100 serum dilution; 9%) levels of cross-neutralizing antibodies. Our results establish that ZIKV and DENV share epitopes that are targeted by neutralizing, protective human antibodies. The availability of potently neutralizing human monoclonal antibodies provides an immunotherapeutic approach to control life-threatening ZIKV infection and also points to the possibility of repurposing DENV vaccines to induce cross-protective immunity to ZIKV.
ZIKV is an emerging arbovirus that has been associated with severe neurological birth defects and fetal loss in pregnant women and Guillain-Barré syndrome in adults. Currently, there is no vaccine or therapeutic for ZIKV. The identification of a class of antibodies (envelope dimer epitope 1 EDE1) that potently neutralizes ZIKV in addition to all four DENV serotypes points to a potential immunotherapeutic to combat ZIKV. This is especially salient given the precedent of antibody therapy to treat pregnant women infected with other viruses associated with microcephaly, such as cytomegalovirus and rubella virus. Furthermore, the identification of a functionally conserved epitope between ZIKV and DENV raises the possibility that a vaccine may be able to elicit neutralizing antibodies against both viruses.
The Kuiper Belt of our solar system is a source of short-period comets that may have delivered water and other volatiles to Earth and the other terrestrial planets. However, the distribution of water ...and other volatiles in extrasolar planetary systems is largely unknown. We report the discovery of an accretion of a Kuiper-Belt-Object analog onto the atmosphere of the white dwarf WD 1425+540. The heavy elements C, N, O, Mg, Si, S, Ca, Fe, and Ni are detected, with nitrogen observed for the first time in extrasolar planetary debris. The nitrogen mass fraction is ~2%, comparable to that in comet Halley and higher than in any other known solar system object. The lower limit to the accreted mass is ~10 super(22) g, which is about one hundred thousand times the typical mass of a short-period comet. In addition, WD 1425+540 has a wide binary companion, which could facilitate perturbing a Kuiper-Belt-Object analog into the white dwarf's tidal radius. This finding shows that analogs to objects in our Kuiper Belt exist around other stars and could be responsible for the delivery of volatiles to terrestrial planets beyond the solar system.
The incidence of chronic kidney disease (CKD) is increasing worldwide, with more than 26 million people suffering from CKD in the United States alone. More patients with CKD die of cardiovascular ...complications than progress to dialysis. Over 80% of CKD patients have hypertension, which is associated with increased risk of cardiovascular morbidity and mortality. Another common, perhaps underappreciated, feature of CKD is an overactive sympathetic nervous system. This elevation in sympathetic nerve activity (SNA) not only contributes to hypertension but also plays a detrimental role in the progression of CKD independent of any increase in blood pressure. Indeed, high SNA is associated with poor prognosis and increased cardiovascular morbidity and mortality independent of its effect on blood pressure. This brief review will discuss some of the consequences of sympathetic overactivity and highlight some of the potential pathways contributing to chronically elevated SNA in CKD. Mechanisms leading to chronic sympathoexcitation in CKD are complex, multifactorial and to date, not completely understood. Identification of the mechanisms and/or signals leading to sympathetic overactivity in CKD are crucial for development of effective therapeutic targets to reduce the increased cardiovascular risk in this patient group.
Many of the static and dynamic properties of an atomic Bose–Einstein condensate (BEC) are usually studied by solving the mean-field Gross–Pitaevskii (GP) equation, which is a nonlinear partial ...differential equation for short-range atomic interaction. More recently, BEC of atoms with long-range dipolar atomic interaction are used in theoretical and experimental studies. For dipolar atomic interaction, the GP equation is a partial integro-differential equation, requiring complex algorithm for its numerical solution. Here we present numerical algorithms for both stationary and non-stationary solutions of the full three-dimensional (3D) GP equation for a dipolar BEC, including the contact interaction. We also consider the simplified one- (1D) and two-dimensional (2D) GP equations satisfied by cigar- and disk-shaped dipolar BECs. We employ the split-step Crank–Nicolson method with real- and imaginary-time propagations, respectively, for the numerical solution of the GP equation for dynamic and static properties of a dipolar BEC. The atoms are considered to be polarized along the z axis and we consider ten different cases, e.g., stationary and non-stationary solutions of the GP equation for a dipolar BEC in 1D (along x and z axes), 2D (in x–y and x–z planes), and 3D, and we provide working codes in Fortran 90/95 and C for these ten cases (twenty programs in all). We present numerical results for energy, chemical potential, root-mean-square sizes and density of the dipolar BECs and, where available, compare them with results of other authors and of variational and Thomas–Fermi approximations.
Program title: (i) imag1dZ, (ii) imag1dX, (iii) imag2dXY, (iv) imag2dXZ, (v) imag3d, (vi) real1dZ, (vii) real1dX, (viii) real2dXY, (ix) real2dXZ, (x) real3d
Catalogue identifier: AEWL_v1_0
Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEWL_v1_0.html
Program obtainable from: CPC Program Library, Queens University, Belfast, N. Ireland
Licensing provisions: Standard CPC licence, http://cpc.cs.qub.ac.uk/licence/licence.html
No. of lines in distributed program, including test data, etc.: 111384
No. of bytes in distributed program, including test data, etc.: 604013
Distribution format: tar.gz
Each year more than 65,000 people are diagnosed with urinary bladder cancer, and more than 14,000 people die from the disease in the United States. Studies in relevant animal models are essential to ...improve the management of bladder cancer. Naturally occurring bladder cancer in dogs very closely mimics human invasive bladder cancer, specifically high-grade invasive transitional cell carcinoma (TCC; also referred to as invasive urothelial carcinoma) in cellular and molecular features; biological behavior, including sites and frequency of metastasis; and response to therapy. Canine bladder cancer complements experimentally induced rodent tumors in regard to animal models of bladder cancer. Results of cellular and molecular studies and -omics analyses in dogs are expected to lead to improved detection of TCC and preneoplastic lesions, earlier intervention, better prediction of patient outcome, and more effective TCC management overall. Studies in dogs are being used to help define heritable risks (through very strong breed-associated risk) and environment risks and to evaluate prevention and treatment approaches that benefit humans as well as dogs. Clinical treatment trials in pet dogs with TCC are considered a win–win scenario by clinician scientists and pet owners. The individual dog benefits from effective treatment, the results are expected to help other dogs, and the findings are expected to ultimately help humans with TCC. This article provides an overview of canine TCC, a summary of the similarities and differences between canine and human invasive TCC, and examples of the types of valuable translational research that can be done using dogs with naturally occurring TCC.
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