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Credit markets, including the market for bank loans, are characterized by imperfect and asymmetric information. These informational frictions can interact with other economic forces to produce periods of credit-market stress, in which intermediation is unusually costly and households and businesses have difficulty obtaining credit. A high level of credit-market stress, as in a severe financial crisis, may in turn produce a deep and prolonged recession. I present evidence that financial distress and disrupted credit markets were important sources of the Great Depression of the 1930s and the Great Recession of 2007–2009. Changes in the state of credit markets also play a role in “ garden-variety” business cycles and in the transmission of monetary policy to the economy. (JEL D82, E32, E44, E52, G21, N22)

Este artículo examina los efectos de la crisis financiera de la década de 1930 en la trayectoria del producto agregado durante ese periodo. La perspectiva es complementaria a la de Friedman y Schwartz, quienes enfatizaron el impacto monetario de las quiebras bancarias; nos enfocamos en los aspectos no monetarios (principalmente relacionados con el crédito) del vínculo entre el sector financiero y el producto, y consideramos los problemas de los deudores, así como los del sistema bancario. Argumentamos que las perturbaciones financieras de 1930-1933 redujeron la eficiencia del proceso de asignación de crédito, y que el mayor costo resultante y la menor disponibilidad de crédito actuaron para deprimir la demanda agregada. La evidencia sugiere que los efectos de este tipo pueden ayudar a explicar las inusuales duración y profundidad de la Gran Depresión.

Monetary policy affects financial markets and the broader economy in part by changing the risk appetite of investors. This article provides new evidence for this so-called risk-taking channel of monetary policy by revisiting and extending event-study analysis of Federal Open Market Committee announcements. We document significant effects of unexpected monetary policy changes on risk indicators drawn from equity, fixed-income, credit, and foreign exchange markets. We develop a new index of risk appetite based on the common component of these indicators. Surprise monetary easing leads to strong and persistent increases in our index, and vice versa for tightening surprises, consistent with the view that monetary policy affects asset prices in large part through its effects on risk appetite. We discuss the implications of the risk-taking channel for monetary policy transmission, optimal monetary policy, and financial stability.

A naive Bayes classifier for identifying Class II YSOs has been constructed and applied to a region of the Northern Galactic Plane containing 8 million sources with good quality Gaia EDR3 parallaxes. The classifier uses the five features: Gaia $G$-band variability, WISE mid-infrared excess, UKIDSS and 2MASS near-infrared excess, IGAPS H$\alpha$ excess and overluminosity with respect to the main sequence. A list of candidate Class II YSOs is obtained by choosing a posterior threshold appropriate to the task at hand, balancing the competing demands of completeness and purity. At a threshold posterior greater than 0.5 our classifier identifies 6504 candidate Class II YSOs. At this threshold we find a false positive rate around 0.02 per cent and a true positive rate of approximately 87 per cent for identifying Class II YSOs. The ROC curve rises rapidly to almost one with an area under the curve around 0.998 or better, indicating the classifier is efficient at identifying candidate Class II YSOs. Our map of these candidates shows what are potentially three previously undiscovered clusters or associations. When comparing our results to published catalogues from other young star classifiers, we find between one quarter and three quarters of high probability candidates are unique to each classifier, telling us no single classifier is finding all young stars., Comment: 38 pages, 28 figures, 15 tables. Accepted for publication in MNRAS

The Event Horizon Telescope (EHT) collaboration has produced the first resolved images of the supermassive black holes at the centre of our galaxy and at the centre of the elliptical galaxy M87. As both technology and analysis pipelines improve, it will soon become possible to produce spectral index maps of black hole accretion flows on event horizon scales. In this work, we predict spectral index maps of both M87* and Sgr A* by applying the general relativistic radiative transfer (GRRT) code IPOLE to a suite of general relativistic magnetohydrodynamic (GRMHD) simulations. We analytically show that the spectral index increases with increasing magnetic field strength, electron temperature, and optical depth. Consequently, spectral index maps grow more negative with increasing radius in almost all models, since all of these quantities tend to be maximised near the event horizon. Additionally, photon ring geodesics exhibit more positive spectral indices, since they sample the innermost regions of the accretion flow with the most extreme plasma conditions. Spectral index maps are sensitive to highly uncertain plasma heating prescriptions (the electron temperature and distribution function). However, if our understanding of these aspects of plasma physics can be tightened, even the spatially unresolved spectral index around 230 GHz can be used to discriminate between models. In particular, Standard and Normal Evolution (SANE) flows tend to exhibit more negative spectral indices than Magnetically Arrested Disk (MAD) flows due to differences in the characteristic magnetic field strength and temperature of emitting plasma., Comment: Accepted for publication in MNRAS

Refereed/Peer-reviewed Cutaneous melanoma is one of the most aggressive forms of skin cancer, with the development of advanced stage disease resulting in a high rate of patient mortality. Accurate diagnosis of melanoma at an early stage is essential to improve patient outcomes, as this enables treatment before the cancer has metastasised. Histopathologic analysis is the current gold standard for melanoma diagnosis, but this can be subjective due to discordance in interpreting the morphological heterogeneity in melanoma and other skin lesions. Immunohistochemistry (IHC) is sometimes employed as an adjunct to conventional histology, but it remains occasionally difficult to distinguish some benign melanocytic lesions and melanoma. Importantly, the complex morphology and lack of specific biomarkers that identify key elements of melanoma pathogenesis can make an accurate confirmation of diagnosis challenging. We review the diagnostic constraints of melanoma heterogeneity and discuss issues with interpreting routine histology and problems with current melanoma markers. Innovative approaches are required to find effective biomarkers to enhance patient management.

We report the analysis of circumbinary discs formed in a radiation hydrodynamical simulation of star cluster formation. We consider both pure binary stars and pairs within triple and quadruple systems. The protostellar systems are all young (ages < $10^5$ yrs). We find that the systems that host a circumbinary disc have a median separation of $\approx 11$ au, and the median characteristic radius of the discs is $\approx 64$ au. We find that $89$ per cent of pure binaries with semi-major axes $a100$ au almost never have a circumbinary disc. The median size of a circumbinary disc is between $\approx 5-6\ a$ depending on the order of the system, with higher order systems having larger discs relative to binary separation. We find the underlying distribution of mutual inclinations between circumbinary discs and binary orbit of both observed and simulated discs to not differ statistically., 12 pages, 11 figures, 1 table, accepted for publication in MNRAS

Purpose: To evaluate AZD4635, an adenosine A2A receptor antagonist, as monotherapy or in combination with durvalumab in patients with advanced solid tumors. Patients and Methods: In phase Ia (dose escalation), patients had relapsed/refractory solid tumors; in phase Ib (dose expansion), patients had checkpoint inhibitor–naïve metastatic castration-resistant prostate cancer (mCRPC) or colorectal carcinoma, non–small cell lung cancer with prior anti–PD-1/PD-L1 exposure, or other solid tumors (checkpoint-naïve or prior anti–PD-1/PD-L1 exposure). Patients received AZD4635 monotherapy (75–200 mg once daily or 125 mg twice daily) or in combination with durvalumab (AZD4635 75 or 100 mg once daily). The primary objective was safety; secondary objectives included antitumor activity and pharmacokinetics; exploratory objectives included evaluation of an adenosine gene signature in patients with mCRPC. Results: As of September 8, 2020, 250 patients were treated (AZD4635, n = 161; AZD4635+durvalumab, n = 89). In phase Ia, DLTs were observed with monotherapy (125 mg twice daily; n = 2) and with combination treatment (75 mg; n = 1) in patients receiving nanosuspension. The most common treatment-related adverse events included nausea, fatigue, vomiting, decreased appetite, dizziness, and diarrhea. The RP2D of the AZD4635 capsule formulation was 75 mg once daily, as monotherapy or in combination with durvalumab. The pharmacokinetic profile was dose-proportional, and exposure was adequate to cover target with 100 mg nanosuspension or 75 mg capsule once daily. In patients with mCRPC receiving monotherapy or combination treatment, tumor responses (2/39 and 6/37, respectively) and prostate-specific antigen responses (3/60 and 10/45, respectively) were observed. High versus low blood-based adenosine signature was associated with median progression-free survival of 21 weeks versus 8.7 weeks. Conclusions: AZD4635 monotherapy or combination therapy was well tolerated. Objective responses support additional phase II combination studies in patients with mCRPC.

Lithium and hydrogen are volatile elements which diffuse rapidly in crystals and melt, making them powerful geochemical tools to reconstruct geological processes that take place on short time scales, such as syn- and post-eruptive degassing. Although the dynamics of hydrogen are fairly well understood to better constrain such processes, the assessment of Li behaviour within the magma reservoir relevant for ascent-related degassing still lacks detailed evaluation. Here, the first in situ Li concentrations and isotopic compositions (using SIMS analysis) of rhyolitic quartz-hosted, naturally glassy and crystallised melt inclusions (MIs) and groundmass glass (Mesa Falls Tuff, Yellowstone) are used to reconstruct Li elemental and isotopic evolution in the magma reservoir. Lithium concentrations in quartz-hosted glassy MIs (10–61 ppm) from a fallout deposit overlap with their groundmass glass (32–46 ppm) and their host quartz (8–15 ppm). Crystallised MIs from a later erupted flow pumice clast sample have higher Li concentrations (8–190 ppm) compared to the groundmass glass (32–51 ppm) and their host quartz (15–24 ppm). Lithium content in quartz from the early erupted sample is relatively homogenous, whereas it is up to a factor of two higher and heterogeneous in the later erupted sample, with a simultaneous increase in Li versus a decrease in H towards crystal rims. The δ7Li difference (expressed as Δ7LiMI–glass) between MIs (−8.0‰ to + 12.3‰) and groundmass glass (+9.0‰ to + 20.5‰) of two pyroclastic deposits reaches up to 29‰. Glassy MIs are internally heterogeneous in δ7Li and Li abundance. The cores of the glassy MIs record the δ7Li of the least modified melt during entrapment and the data distribution can be modelled by equilibrium fractionation between the melt and vapour phase during early open-system degassing in the magma reservoir. Late degassing during eruption triggers Li–H diffusional exchange between quartz and melt, as the degassing of H2O and the accompanying pressure change trigger H diffusion out of the host quartz and the MIs, which is charge balanced by inward Li diffusion. This results in the modification of Li contents in quartz and δ7Li values in the rims of the glassy MIs. Crystallised MIs reflect the loss of H2O from the MIs and the resulting enrichment of Li during the crystallisation. Additionally, the variations of δ7Li in the groundmass glass can be explained through modelling by kinetic fractionation between the melt and vapour during late stage open-system degassing linked with magma ascent. ISSN:0016-7037 ISSN:1872-9533

Consumer-based voice assistants have the ability to deliver evidence-based treatment, but their therapeutic potential is largely unknown. In a pilot trial of a virtual voice-based coach, Lumen, delivering problem-solving treatment, adults with mild-to-moderate depression and/or anxiety were randomized to the Lumen intervention (n = 42) or waitlist control (n = 21). The main outcomes included changes in neural measures of emotional reactivity and cognitive control, and Hospital Anxiety and Depression Scale [HADS] symptom scores over 16 weeks. Participants were 37.8 years (SD = 12.4), 68% women, 25% Black, 24% Latino, and 11% Asian. Activation of the right dlPFC (neural region of interest in cognitive control) decreased in the intervention group but increased in the control group, with an effect size meeting the prespecified threshold for a meaningful effect (Cohen’s d = 0.3). Between-group differences in the change in activation of the left dlPFC and bilateral amygdala were observed, but were of smaller magnitude (d = 0.2). Change in right dlPFC activation was also meaningfully associated (r ≥ 0.4) with changes in self-reported problem-solving ability and avoidance in the intervention. Lumen intervention also led to decreased HADS depression, anxiety, and overall psychological distress scores, with medium effect sizes (Cohen’s d = 0.49, 0.51, and 0.55, respectively), compared with the waitlist control group. This pilot trial showed promising effects of a novel digital mental health intervention on cognitive control using neuroimaging and depression and anxiety symptoms, providing foundational evidence for a future confirmatory study.

PDF file - 110K, Supplemental Tables. (S1) Clinical characteristics and CTC data for metastatic prostate cancer patients treated with hormonal therapy. (S2) Time course data for metastatic prostate cancer patients treated with hormonal therapy and analyzed for AR signaling in CTCs.

Figure S3. Illustration of modeling and correcting for dependence of each marker through the expression level of housekeeping genes.

Figure S5. Knockdown of MAPK7, CDC7, CDC2L5 and CSNKID induces Mesenchymal-Epithelial Transition (MET).

Supplementary Table S1: Patients and clinical information. Supplementary Table S2: Genes used to determine the AR signature.

Table S3

Figure S2. Scatter-plots showing a linear relationship between expression of housekeeping genes.

Table S8

Supplementary Information

All supplementary tables

All supplementary figures

Table S2

Table S7

Figure S1. Summary of kinome screen.

Figure S4. Heat map analysis of the kinome screen generated by the Wilcoxon method.

Methods describing microfluidic CTC enrichment, RNA extraction, amplification and detection, single cell and bulk RNA sequencing

Supplementary Figure S1: RNA sequencing and pathway analysis of CTCs from Bone(+) versus Visceral(+) breast cancer patients. Supplementary Figure S2: Correlation between AR expression and AR signatures. Supplementary Figure S3: ER and PR expression in CTCs from Bone(+) versus Visceral(+) breast cancer patients. Supplementary Figure S4: AR antibody validation. Supplementary Figure S5: AR copy number assessment in breast cancer bone metastasis. Supplementary Figure S6: ER and PR expression in primary and metastatic breast cancer. Supplementary Figure S7: AR expression correlates with bone metastasis independently of ER status. Supplementary Figure S8: Enzalutamide treatment induces downregulation of a subset of AR-dependent genes in breast cancer cells. Supplementary Figure S9: AR shRNA validation. Supplementary Figure S10: AR inhibition does not alter primary tumor growth.

Figure S6. Knockdown of MAPK7 does not increase proliferation rate in primary tumor or lung metastasis.

Supplemental Methods, Tables S1-2, Table Legends and Figure Legends Table S1.List of qRT-PCR primers used for epithelial, mesenchymal, inducer and housekeeping genes. Table S2. RNA-ISH quantitation of expression scores used in Figure 5.

PDF file - 49K, Supplemental Methods for (a) single molecule sequencing and AR transcriptional signature, (b) HB CTC-chip fabrication, (c) HB CTC-chip blood processing, and (d) automated fluorescence microscopy.

Table S5

Table S4

Table S6

Supplementary Table from Phase Ia/b, Open-Label, Multicenter Study of AZD4635 (an Adenosine A2A Receptor Antagonist) as Monotherapy or Combined with Durvalumab, in Patients with Solid Tumors

Purpose:To evaluate AZD4635, an adenosine A2A receptor antagonist, as monotherapy or in combination with durvalumab in patients with advanced solid tumors.Patients and Methods:In phase Ia (dose escalation), patients had relapsed/refractory solid tumors; in phase Ib (dose expansion), patients had checkpoint inhibitor–naïve metastatic castration-resistant prostate cancer (mCRPC) or colorectal carcinoma, non–small cell lung cancer with prior anti–PD-1/PD-L1 exposure, or other solid tumors (checkpoint-naïve or prior anti–PD-1/PD-L1 exposure). Patients received AZD4635 monotherapy (75–200 mg once daily or 125 mg twice daily) or in combination with durvalumab (AZD4635 75 or 100 mg once daily). The primary objective was safety; secondary objectives included antitumor activity and pharmacokinetics; exploratory objectives included evaluation of an adenosine gene signature in patients with mCRPC.Results:As of September 8, 2020, 250 patients were treated (AZD4635, n = 161; AZD4635+durvalumab, n = 89). In phase Ia, DLTs were observed with monotherapy (125 mg twice daily; n = 2) and with combination treatment (75 mg; n = 1) in patients receiving nanosuspension. The most common treatment-related adverse events included nausea, fatigue, vomiting, decreased appetite, dizziness, and diarrhea. The RP2D of the AZD4635 capsule formulation was 75 mg once daily, as monotherapy or in combination with durvalumab. The pharmacokinetic profile was dose-proportional, and exposure was adequate to cover target with 100 mg nanosuspension or 75 mg capsule once daily. In patients with mCRPC receiving monotherapy or combination treatment, tumor responses (2/39 and 6/37, respectively) and prostate-specific antigen responses (3/60 and 10/45, respectively) were observed. High versus low blood-based adenosine signature was associated with median progression-free survival of 21 weeks versus 8.7 weeks.Conclusions:AZD4635 monotherapy or combination therapy was well tolerated. Objective responses support additional phase II combination studies in patients with mCRPC.

Supplementary Figure from Phase Ia/b, Open-Label, Multicenter Study of AZD4635 (an Adenosine A2A Receptor Antagonist) as Monotherapy or Combined with Durvalumab, in Patients with Solid Tumors

Purpose: Most node-negative breast cancer patients are older and postmenopausal and are increasingly being offered adjuvant chemotherapy despite their low overall risk of distant relapse. A molecular diagnostic test with high negative predictive value (NPV) for distant metastasis in this subgroup would spare many older breast cancer patients adjuvant treatment.Experimental Design: We determined the NPV and positive predictive value of the MammaPrint assay in breast cancer patients who were consecutively diagnosed and treated at the Massachusetts General Hospital between 1985 and 1997. Primary tumors from 100 patients with node-negative, invasive breast cancer (median age, 62.5 years; median follow-up, 11.3 years) were subjected to MammaPrint analysis and classified as being at either low or high risk for distant metastasis.Results: The MammaPrint 70-gene signature displayed excellent NPV as in previous studies, correctly identifying 100% of women at low risk for distant metastases at 5 years. However, this assay had a lower positive predictive value (12% at 5 years) than previously observed.Conclusions: The MammaPrint assay was originally designed to identify younger breast cancer patients at low risk for distant metastasis, who might consequently be spared systemic treatment. We show here that the same signature has a very high NPV for distant recurrence after adjuvant treatment in older breast cancer patients.

Supplementary Table S1 from Analysis of the MammaPrint Breast Cancer Assay in a Predominantly Postmenopausal Cohort

Supplementary Figure 6 from Centrosomal PKCβII and Pericentrin Are Critical for Human Prostate Cancer Growth and Angiogenesis

Supplementary Figure 4 from Centrosomal PKCβII and Pericentrin Are Critical for Human Prostate Cancer Growth and Angiogenesis

Supplementary Figure 5 from Centrosomal PKCβII and Pericentrin Are Critical for Human Prostate Cancer Growth and Angiogenesis

Supplementary Figure 1 from Centrosomal PKCβII and Pericentrin Are Critical for Human Prostate Cancer Growth and Angiogenesis

Supplementary Figure 3 from Centrosomal PKCβII and Pericentrin Are Critical for Human Prostate Cancer Growth and Angiogenesis

Supplementary Figure 2 from Centrosomal PKCβII and Pericentrin Are Critical for Human Prostate Cancer Growth and Angiogenesis

Angiogenesis is critical in the progression of prostate cancer. However, the interplay between the proliferation kinetics of tumor endothelial cells (angiogenesis) and tumor cells has not been investigated. Also, protein kinase C (PKC) regulates various aspects of tumor cell growth, but its role in prostate cancer has not been investigated in detail. Here, we found that the proliferation rates of endothelial and tumor cells oscillate asynchronously during the growth of human prostate cancer xenografts. Furthermore, our analyses suggest that PKCβII was activated during increased angiogenesis and that PKCβII plays a key role in the proliferation of endothelial cells and tumor cells in human prostate cancer; treatment with a PKCβII-selective inhibitor, βIIV5-3, reduced angiogenesis and tumor cell proliferation. We also find a unique effect of PKCβII inhibition on normalizing pericentrin (a protein regulating cytokinesis), especially in endothelial cells as well as in tumor cells. PKCβII inhibition reduced the level and mislocalization of pericentrin and normalized microtubule organization in the tumor endothelial cells. Although pericentrin has been known to be up-regulated in epithelial cells of prostate cancers, its level in tumor endothelium has not been studied in detail. We found that pericentrin is up-regulated in human tumor endothelium compared with endothelium adjacent to normal glands in tissues from prostate cancer patients. Our results suggest that a PKCβII inhibitor such as βIIV5-3 may be used to reduce prostate cancer growth by targeting both angiogenesis and tumor cell growth. [Cancer Res 2008;68(16):6831–9]

Equitable global access to vaccines requires we overcome challenges associated with complex immunization schedules and their associated economic burdens that hinder delivery in under resourced environments. The rabies vaccine, for example, requires multiple immunizations for effective protection and each dose is cost prohibitive, and therefore inaccessibility disproportionately impacts low- and middle-income countries. In this work we developed an injectable hydrogel depot technology for sustained delivery of commercial inactivated rabies virus vaccines. In a mouse model, we showed that a single immunization of a hydrogel-based rabies vaccine elicited comparable antibody titers to a standard prime-boost bolus regimen of a commercial rabies vaccine, despite these hydrogel vaccines comprising only half of the total dose delivered in the bolus control. Moreover, these hydrogel-based vaccines elicited similar antigen-specific T-cell responses and neutralizing antibody responses compared to the bolus vaccine. Notably, we demonstrated that while addition of a potent clinical TLR4 agonist adjuvant to the gels slightly improved binding antibody responses, inclusion of this adjuvant to the inactivated virion vaccine was detrimental to neutralizing responses. Taken together, these results suggest that these hydrogels can enable an effective regimen compression and dosesparing strategy for improving global access to vaccines.