Research on psychopathy has progressed considerably in recent years against the backdrop of important advances in the broader field of clinical psychological science. My major aim in this review is ...to encourage integration of investigative work on dispositional, biobehavioral, and developmental aspects of psychopathy with counterpart work on general psychopathology. Using the triarchic model of psychopathy as a frame of reference, I offer perspective on long-standing debates pertaining to the conceptualization and assessment of psychopathy, discuss how dispositional facets of psychopathy relate to subdimensions of internalizing and externalizing psychopathology, and summarize findings from contemporary biobehavioral and developmental research on psychopathy. I conclude by describing a systematic strategy for coordinating biobehavioral-developmental research on psychopathy that can enable it to be informed by, and help inform, ongoing research on mental health problems more broadly.
ABSTRACT We report the discovery of three large ( 1′) extremely low surface brightness (LSB; ) galaxies identified using our deep, wide-field imaging of the Virgo Cluster from the Burrell Schmidt ...telescope. Complementary data from the Next Generation Virgo Cluster Survey do not resolve red giant branch stars in these objects down to i = 24, yielding a lower distance limit of 2.5 Mpc. At the Virgo distance, these objects have half-light radii 3-10 kpc and luminosities = 2-9 × 107 . These galaxies are comparable in size but lower in surface brightness than the large ultradiffuse LSB galaxies recently identified in the Coma cluster, and are located well within Virgo's virial radius; two are projected directly on the cluster core. One object appears to be a nucleated LSB in the process of being tidally stripped to form a new Virgo ultracompact dwarf galaxy. The others show no sign of tidal disruption, despite the fact that such objects should be most vulnerable to tidal destruction in the cluster environment. The relative proximity of Virgo makes these objects amenable to detailed studies of their structural properties and resolved stellar populations. They thus provide an important new window onto the connection between cluster environment and galaxy evolution at the extremes.
Forecasts and alternative scenarios of COVID-19 mortality have been critical inputs for pandemic response efforts, and decision-makers need information about predictive performance. We screen n = 386 ...public COVID-19 forecasting models, identifying n = 7 that are global in scope and provide public, date-versioned forecasts. We examine their predictive performance for mortality by weeks of extrapolation, world region, and estimation month. We additionally assess prediction of the timing of peak daily mortality. Globally, models released in October show a median absolute percent error (MAPE) of 7 to 13% at six weeks, reflecting surprisingly good performance despite the complexities of modelling human behavioural responses and government interventions. Median absolute error for peak timing increased from 8 days at one week of forecasting to 29 days at eight weeks and is similar for first and subsequent peaks. The framework and public codebase ( https://github.com/pyliu47/covidcompare ) can be used to compare predictions and evaluate predictive performance going forward.
Adipose-resident T cells (ARTs) regulate metabolic and inflammatory responses in obesity, but ART activation signals are poorly understood. Here, we describe class II major histocompatibility complex ...(MHCII) as an important component of high-fat-diet (HFD)-induced obesity. Microarray analysis of primary adipocytes revealed that multiple genes involved in MHCII antigen processing and presentation increased in obese women. In mice, adipocyte MHCII increased within 2 weeks on HFD, paralleling increases in proinflammatory ART markers and decreases in anti-inflammatory ART markers, and preceding adipose tissue macrophage (ATM) accumulation and proinflammatory M1 polarization. Mouse 3T3-L1 and primary adipocytes activated T cells in an antigen-specific, contact-dependent manner, indicating that adipocyte MHCII is functional. HFD-fed MHCII−/− mice developed less adipose inflammation and insulin resistance than did wild-type mice, despite developing similar adiposity. These investigations uncover a mechanism whereby a HFD-induced adipocyte/ART dialog involving MHCII instigates adipose inflammation and, together with ATM MHCII, escalates its progression.
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► Obesity enhances MHCII expression in primary human and mouse adipocytes ► Adipocytes activate CD4+ ARTs via MHCII and leptin to induce adipose inflammation ► Macrophage changes in adipose follow adipocyte and T cell interactions during HFD ► Adaptive immune mechanisms are essential to obesity-induced adipose inflammation
Herein, we describe the design and synthesis of γ-secretase modulator (GSM) clinical candidate PF-06648671 (22) for the treatment of Alzheimer’s disease. A key component of the design involved a ...2,5-cis-tetrahydrofuran (THF) linker to impart conformational rigidity and lock the compound into a putative bioactive conformation. This effort was guided using a pharmacophore model since crystallographic information was not available for the membrane-bound γ-secretase protein complex at the time of this work. PF-06648671 achieved excellent alignment of whole cell in vitro potency (Aβ42 IC50 = 9.8 nM) and absorption, distribution, metabolism, and excretion (ADME) parameters. This resulted in favorable in vivo pharmacokinetic (PK) profile in preclinical species, and PF-06648671 achieved a human PK profile suitable for once-a-day dosing. Furthermore, PF-06648671 was found to have favorable brain availability in rodent, which translated into excellent central exposure in human and robust reduction of amyloid β (Aβ) 42 in cerebrospinal fluid (CSF).
Misfolded proteins compromise cellular homeostasis. This is especially problematic in the endoplasmic reticulum (ER), which is a high-capacity protein-folding compartment and whose function requires ...stringent protein quality-control systems. Multiprotein complexes in the ER are able to identify, remove, ubiquitinate, and deliver misfolded proteins to the 26S proteasome for degradation in the cytosol, and these events are collectively termed ER-associated degradation, or ERAD. Several steps in the ERAD pathway are facilitated by molecular chaperone networks, and the importance of ERAD is highlighted by the fact that this pathway is linked to numerous protein conformational diseases. In this review, we discuss the factors that constitute the ERAD machinery and detail how each step in the pathway occurs. We then highlight the underlying pathophysiology of protein conformational diseases associated with ERAD.
Insecticide-treated nets (ITNs) and indoor residual spraying (IRS) represent the front-line tools for malaria vector control globally, but are optimally effective where the majority of baseline ...transmission occurs indoors. In the surveyed area of rural southern Tanzania, bed net use steadily increased over the last decade, reducing malaria transmission intensity by 94%.
Starting before bed nets were introduced (1997), and then after two milestones of net use had been reached-75% community-wide use of untreated nets (2004) and then 47% use of ITNs (2009)-hourly biting rates of malaria vectors from the Anopheles gambiae complex and Anopheles funestus group were surveyed.
In 1997, An. gambiae s.l. and An. funestus mosquitoes exhibited a tendency to bite humans inside houses late at night. For An. gambiae s.l., by 2009, nocturnal activity was less (p = 0.0018). At this time, the sibling species composition of the complex had shifted from predominantly An. gambiae s.s. to predominantly An. arabiensis. For An. funestus, by 2009, nocturnal activity was less (p = 0.0054) as well as the proportion biting indoors (p < 0.0001). At this time, An. funestus s.s. remained the predominant species within this group. As a consequence of these altered feeding patterns, the proportion (mean ± standard error) of human contact with mosquitoes (bites per person per night) occurring indoors dropped from 0.99 ± 0.002 in 1997 to 0.82 ± 0.008 in 2009 for the An. gambiae complex (p = 0.0143) and from 1.00 ± <0.001 to only 0.50 ± 0.048 for the An. funestus complex (p = 0.0004) over the same time period.
High usage of ITNs can dramatically alter African vector populations so that intense, predominantly indoor transmission is replaced by greatly lowered residual transmission, a greater proportion of which occurs outdoors. Regardless of the underlying mechanism, the residual, self-sustaining transmission will respond poorly to further insecticidal measures within houses. Additional vector control tools which target outdoor biting mosquitoes at the adult or immature stages are required to complement ITNs and IRS.
Humans strongly impact the dynamics of coastal systems, yet surprisingly few studies mechanistically link management of anthropogenic stressors and successful restoration of nearshore habitats over ...large spatial and temporal scales. Such examples are sorely needed to ensure the success of ecosystem restoration efforts worldwide. Here, we unite 30 consecutive years of watershed modeling, biogeochemical data, and comprehensive aerial surveys of Chesapeake Bay, United States to quantify the cascading effects of anthropogenic impacts on submersed aquatic vegetation (SAV), an ecologically and economically valuable habitat. We employ structural equation models to link land use change to higher nutrient loads, which in turn reduce SAV cover through multiple, independent pathways. We also show through our models that high biodiversity of SAV consistently promotes cover, an unexpected finding that corroborates emerging evidence from other terrestrial and marine systems. Due to sustained management actions that have reduced nitrogen concentrations in Chesapeake Bay by 23% since 1984, SAV has regained 17,000 ha to achieve its highest cover in almost half a century. Our study empirically demonstrates that nutrient reductions and biodiversity conservation are effective strategies to aid the successful recovery of degraded systems at regional scales, a finding which is highly relevant to the utility of environmental management programs worldwide.
The triarchic model (Patrick, Fowles, & Krueger, 2009) was formulated to reconcile contrasting conceptions of psychopathy reflected in historic writings and contemporary assessment instruments, and ...to address persisting unresolved issues in the field. The model conceives of psychopathy as encompassing three distinct but interrelated phenotypic dispositions—disinhibition, boldness, and meanness—with biological referents. These dispositional constructs can be viewed as building blocks for alternative conceptions of psychopathy, and various existing psychopathy measures are presumed to index these constructs to differing degrees. This article summarizes the bases of the triarchic model in the conceptual and empirical literatures on psychopathy, and it describes linkages between the constructs of the model and established structural frameworks for personality and psychological disorders. Alternative methods for indexing the constructs of the model are described, and evidence regarding their interrelations and criterion‐related validity is reviewed. Promising aspects of the model for ongoing research on psychopathy are discussed, along with current gaps in knowledge/methods and recommended avenues for future research.
As highlighted by articles in the current special issue, the RDoC initiative holds promise for advancing understanding of mental health problems. However, the initiative is at its early stages and it ...remains unclear what level of progress can be achieved and how quickly. In this closing article, we identify major challenges facing RDoC and propose concrete approaches to addressing these challenges, including (a) clearer specification of clinical problems for study, with use of symptom dimensions from integrative dimensional models of psychopathology as provisional, modifiable referents; (b) encouragement of research on a distinct set of traits corresponding to process constructs from the RDoC matrix—those represented across animal, child temperament, and adult personality literatures—to serve as interfaces between matrix constructs and clinical problems; (c) an emphasis in the near term on use of proximal units of analysis in RDoC studies—in particular, on physiological, behavioral, and self‐report measures of matrix constructs (examined as states or traits, or both); (d) inclusion of a clear ontogenetic‐developmental component in RDoC research projects; (e) routine analysis of the psychometric properties of nonreport (e.g., physiological, task‐behavioral) variables, including systematic evaluation of their reliability and convergent‐discriminant validity; (f) modification of existing grant review criteria to prioritize replication and synergy in RDoC investigative work; and (g) creation of a cumulative data network system (RDoC–DataWeb) to encourage and facilitate coordination of research efforts across RDoC research groups.
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