Sorting Guilty Minds

Because punishable guilt requires that bad thoughts accompany bad acts, the Model Penal Code (MPC) typically requires that jurors infer the past mental state of a criminal defendant. More specifically, jurors must sort that mental state into one of four specific categories - purposeful, knowing, reckless, or negligent - which in turn defines the nature of the crime and the extent of the punishment. The MPC therefore assumes that ordinary people naturally sort mental states into these four categories with a high degree of accuracy, or at least can reliably do so when properly instructed. It also assumes that ordinary people will order these categories of mental state, by increasing amount of punishment, in the same severity hierarchy that the MPC prescribes. The MPC, now turning 50 years old, has previously escaped the scrutiny of comprehensive empirical research on these assumptions underlying its culpability architecture. Our new empirical studies, reported here, find that most of the mens rea assumptions embedded in the MPC are reasonably accurate as a behavioral matter. Even without the aid of the MPC definitions, subjects were able to regularly and accurately distinguish among purposeful, negligent, and blameless conduct. Nevertheless, our subjects failed to distinguish reliably between knowing and reckless conduct. This failure can have significant sentencing consequences in some types of crimes, especially homicide

Lipopolysaccharide impairs amyloid β efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood-brain barrier

BACKGROUND: Defects in the low density lipoprotein receptor-related protein-1 (LRP-1) and p-glycoprotein (Pgp) clearance of amyloid beta (Aβ) from brain are thought to contribute to Alzheimer\u27s disease (AD). We have recently shown that induction of systemic inflammation by lipopolysaccharide (LPS) results in impaired efflux of Aβ from the brain. The same treatment also impairs Pgp function. Here, our aim is to determine which physiological routes of Aβ clearance are affected following systemic inflammation, including those relying on LRP-1 and Pgp function at the blood-brain barrier. METHODS: CD-1 mice aged between 6 and 8 weeks were treated with 3 intraperitoneal injections of 3 mg/kg LPS at 0, 6, and 24 hours and studied at 28 hours. 125I-Aβ1-42 or 125I-alpha-2-macroglobulin injected into the lateral ventricle of the brain (intracerebroventricular (ICV)) or into the jugular vein (intravenous (IV)) was used to quantify LRP-1-dependent partitioning between the brain vasculature and parenchyma and peripheral clearance, respectively. Disappearance of ICV-injected 14 C-inulin from brain was measured to quantify bulk flow of cerebrospinal fluid (CSF). Brain microvascular protein expression of LRP-1 and Pgp was measured by immunoblotting. Endothelial cell localization of LRP-1 was measured by immunofluorescence microscopy. Oxidative modifications to LRP-1 at the brain microvasculature were measured by immunoprecipitation of LRP-1 followed by immunoblotting for 4-hydroxynonenal and 3-nitrotyrosine. RESULTS: We found that LPS: caused an LRP-1-dependent redistribution of ICV-injected Aβ from brain parenchyma to brain vasculature and decreased entry into blood; impaired peripheral clearance of IV-injected Aβ; inhibited reabsorption of CSF; did not significantly alter brain microvascular protein levels of LRP-1 or Pgp, or oxidative modifications to LRP-1; and downregulated LRP-1 protein levels and caused LRP-1 mislocalization in cultured brain endothelial cells. CONCLUSIONS: These results suggest that LRP-1 undergoes complex functional regulation following systemic inflammation which may depend on cell type, subcellular location, and post-translational modifications. Our findings that systemic inflammation causes deficits in both Aβ transport and bulk flow like those observed in AD indicate that inflammation could induce and promote the disease

Help or hinder: Bayesian models of social goal inference

Everyday social interactions are heavily influenced by our snap judgments about others’ goals. Even young infants can infer the goals of intentional agents from observing how they interact with objects and other agents in their environment: e.g., that one agent is ‘helping’ or ‘hindering’ another’s attempt to get up a hill or open a box. We propose a model for how people can infer these social goals from actions, based on inverse planning in multiagent Markov decision problems (MDPs). The model infers the goal most likely to be driving an agent’s behavior by assuming the agent acts approximately rationally given environmental constraints and its model of other agents present. We also present behavioral evidence in support of this model over a simpler, perceptual cue-based alternative.United States. Army Research Office (ARO MURI grant W911NF-08-1-0242)United States. Air Force Office of Scientific Research (MURI grant FA9550-07-1-0075)National Science Foundation (U.S.) (Graduate Research Fellowship)James S. McDonnell Foundation (Collaborative Interdisciplinary Grant on Causal Reasoning

The Potential Impact of Nuclear Conflict on Ocean Acidification

We demonstrate that the global cooling resulting from a range of nuclear conflict scenarios would temporarily increase the pH in the surface ocean by up to 0.06 units over a 5-year period, briefly alleviating the decline in pH associated with ocean acidification. Conversely, the global cooling dissolves atmospheric carbon into the upper ocean, driving a 0.1 to 0.3 unit decrease in the aragonite saturation state (Ωarag) that persists for ∼10 years. The peak anomaly in pH occurs 2 years post conflict, while the Ωarag anomaly peaks 4- to 5-years post conflict. The decrease in Ωarag would exacerbate a primary threat of ocean acidification: the inability of marine calcifying organisms to maintain their shells/skeletons in a corrosive environment. Our results are based on sensitivity simulations conducted with a state-of-the-art Earth system model integrated under various black carbon (soot) external forcings. Our findings suggest that regional nuclear conflict may have ramifications for global ocean acidification

Variability in X-ray induced effects in [Rh(COD)Cl]₂ with changing experimental parameters

X-ray characterisation methods have undoubtedly enabled cutting-edge advances in all aspects of materials research. Despite the enormous breadth of information that can be extracted from these techniques, the challenge of radiation-induced sample change and damage remains prevalent. This is largely due to the emergence of modern, high-intensity X-ray source technologies and the growing potential to carry out more complex, longer duration in situ or in operando studies. The tunability of synchrotron beamlines enables the routine application of photon energy-dependent experiments. This work explores the structural stability of [Rh(COD)Cl]2, a widely used catalyst and precursor in the chemical industry, across a range of beamline parameters that target X-ray energies of 8 keV, 15 keV, 18 keV and 25 keV, on a powder X-ray diffraction synchrotron beamline at room temperature. Structural changes are discussed with respect to absorbed X-ray dose at each experimental setting associated with the respective photon energy. In addition, the X-ray radiation hardness of the catalyst is discussed, by utilising the diffraction data collected at the different energies to determine a dose limit, which is often considered in protein crystallography and typically overlooked in small molecule crystallography. This work not only gives fundamental insight into how damage manifests in this organometallic catalyst, but will encourage careful consideration of experimental X-ray parameters before conducting diffraction on similar radiation-sensitive organometallic materials

Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer‐related mortality. Despite significant advances made in the treatment of other cancers, current chemotherapies offer little survival benefit in this disease. Pancreaticoduodenectomy offers patients the possibility of a cure, but most will die of recurrent or metastatic disease. Hence, preventing metastatic disease in these patients would be of significant benefit. Using principal component analysis (PCA), we identified a LOX/hypoxia signature associated with poor patient survival in resectable patients. We found that LOX expression is upregulated in metastatic tumors from Pdx1‐Cre KrasG12D/+ Trp53R172H/+ (KPC) mice and that inhibition of LOX in these mice suppressed metastasis. Mechanistically, LOX inhibition suppressed both migration and invasion of KPC cells. LOX inhibition also synergized with gemcitabine to kill tumors and significantly prolonged tumor‐free survival in KPC mice with early‐stage tumors. This was associated with stromal alterations, including increased vasculature and decreased fibrillar collagen, and increased infiltration of macrophages and neutrophils into tumors. Therefore, LOX inhibition is able to reverse many of the features that make PDAC inherently refractory to conventional therapies and targeting LOX could improve outcome in surgically resectable disease

Platelet actin nodules are podosome-like structures dependent on Wiskott-Aldrich syndrome protein and ARP2/3 complex

The actin nodule is a novel F-actin structure present in platelets during early spreading. However, only limited detail is known regarding nodule organization and function. Here we use electron microscopy, SIM and dSTORM super-resolution, and live-cell TIRF microscopy to characterize the structural organization and signalling pathways associated with nodule formation. Nodules are composed of up to four actin-rich structures linked together by actin bundles. They are enriched in the adhesion-related proteins talin and vinculin, have a central core of tyrosine phosphorylated proteins and are depleted of integrins at the plasma membrane. Nodule formation is dependent on Wiskott-Aldrich syndrome protein (WASp) and the ARP2/3 complex. WASp(-/-) mouse blood displays impaired platelet aggregate formation at arteriolar shear rates. We propose actin nodules are platelet podosome-related structures required for platelet-platelet interaction and their absence contributes to the bleeding diathesis of Wiskott-Aldrich syndrome

Marine wild-capture fisheries after nuclear war

Unidad de excelencia María de Maeztu CEX2019-000940-MIdentificadors digitals: Digital object identifier for the 'European Research Council' (http://dx.doi.org/10.13039/501100000781) Digital object identifier for 'Horizon 2020' (http://dx.doi.org/10.13039/501100007601) - BIGSEA projectNuclear war, beyond its devastating direct impacts, is expected to cause global climatic perturbations through injections of soot into the upper atmosphere. Reduced temperature and sunlight could drive unprecedented reductions in agricultural production, endangering global food security. However, the effects of nuclear war on marine wild-capture fisheries, which significantly contribute to the global animal protein and micronutrient supply, remain unexplored. We simulate the climatic effects of six war scenarios on fish biomass and catch globally, using a state-of-the-art Earth system model and global process-based fisheries model. We also simulate how either rapidly increased fish demand (driven by food shortages) or decreased ability to fish (due to infrastructure disruptions), would affect global catches, and test the benefits of strong prewar fisheries management. We find a decade-long negative climatic impact that intensifies with soot emissions, with global biomass and catch falling by up to 18 ± 3% and 29 ± 7% after a US-Russia war under business-as-usual fishing-similar in magnitude to the end-of-century declines under unmitigated global warming. When war occurs in an overfished state, increasing demand increases short-term (1 to 2 y) catch by at most ∼30% followed by precipitous declines of up to ∼70%, thus offsetting only a minor fraction of agricultural losses. However, effective prewar management that rebuilds fish biomass could ensure a short-term catch buffer large enough to replace ∼43 ± 35% of today's global animal protein production. This buffering function in the event of a global food emergency adds to the many previously known economic and ecological benefits of effective and precautionary fisheries management

Marine wild-capture fisheries after nuclear war

Nuclear war, beyond its devastating direct impacts, is expected to cause global climatic perturbations through injections of soot into the upper atmosphere. Reduced temperature and sunlight could drive unprecedented reductions in agricultural production, endangering global food security. However, the effects of nuclear war on marine wild-capture fisheries, which significantly contribute to the global animal protein and micronutrient supply, remain unexplored. We simulate the climatic effects of six war scenarios on fish biomass and catch globally, using a state-of-the-art Earth system model and global process-based fisheries model. We also simulate how either rapidly increased fish demand (driven by food shortages) or decreased ability to fish (due to infrastructure disruptions), would affect global catches, and test the benefits of strong prewar fisheries management. We find a decade-long negative climatic impact that intensifies with soot emissions, with global biomass and catch falling by up to 18 ± 3% and 29 ± 7% after a US–Russia war under business-as-usual fishing—similar in magnitude to the end-of-century declines under unmitigated global warming. When war occurs in an overfished state, increasing demand increases short-term (1 to 2 y) catch by at most ∼30% followed by precipitous declines of up to ∼70%, thus offsetting only a minor fraction of agricultural losses. However, effective prewar management that rebuilds fish biomass could ensure a short-term catch buffer large enough to replace ∼43 ± 35% of today’s global animal protein production. This buffering function in the event of a global food emergency adds to the many previously known economic and ecological benefits of effective and precautionary fisheries management

A New Ocean State After Nuclear War

Nuclear war would produce dire global consequences for humans and our environment. We simulated climate impacts of US-Russia and India-Pakistan nuclear wars in an Earth System Model, here, we report on the ocean impacts. Like volcanic eruptions and large forest fires, firestorms from nuclear war would transport light-blocking aerosols to the stratosphere, resulting in global cooling. The ocean responds over two timescales: a rapid cooling event and a long recovery, indicating a hysteresis response of the ocean to global cooling. Surface cooling drives sea ice expansion, enhanced meridional overturning, and intensified ocean vertical mixing that is expanded, deeper, and longer lasting. Phytoplankton production and community structure are highly modified by perturbations to light, temperature, and nutrients, resulting in initial decimation of production, especially at high latitudes. A new physical and biogeochemical ocean state results, characterized by shallower pycnoclines, thermoclines, and nutriclines, ventilated deep water masses, and thicker Arctic sea ice. Persistent changes in nutrient limitation drive a shift in phytoplankton community structure, resulting in increased diatom populations, which in turn increase iron scavenging and iron limitation, especially at high latitudes. In the largest US-Russia scenario (150 Tg), ocean recovery is likely on the order of decades at the surface and hundreds of years at depth, while changes to Arctic sea-ice will likely last thousands of years, effectively a “Nuclear Little Ice Age.” Marine ecosystems would be highly disrupted by both the initial perturbation and in the new ocean state, resulting in long-term, global impacts to ecosystem services such as fisheries.publishedVersio