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Fear is an adaptive emotion that serves to protect an organism against potential dangers. It is often studied using classical conditioning paradigms where a conditioned stimulus is paired with an aversive unconditioned stimulus to induce a threat response. Less commonly studied is a phenomenon that is related to this form of conditioning, known as latent inhibition. Latent inhibition (LI) is a paradigm in which a neutral cue is repeatedly presented in the absence of any aversive associations. Subsequent pairing of this pre-exposed cue with an aversive stimulus typically leads to reduced expression of a conditioned fear/threat response. In this article, we review some of the theoretical basis for LI and its behavioral and neural mechanisms. We compare and contrast LI and fear/threat extinction--a process in which a previously conditioned cue is repeatedly presented in the absence of aversive outcomes. We end with highlighting the potential clinical utility of LI. Particularly, we focus on how LI application could be useful for enhancing resilience, especially for individuals who are more prone to continuous exposure to trauma and stressful environments, such as healthcare workers and first responders. The knowledge to be gained from advancing our understanding of neural mechanisms in latent inhibition could be applicable across psychiatric disorders characterized by exaggerated fear responses and impaired emotion regulation.

The brain is an endocrine organ, sensitive to the rhythmic changes in sex hormone production that occurs in most mammalian species. In rodents and nonhuman primates, estrogen and progesterone's impact on the brain is evident across a range of spatiotemporal scales. Yet, the influence of sex hormones on the functional architecture of the human brain is largely unknown. In this dense-sampling, deep phenotyping study, we examine the extent to which endogenous fluctuations in sex hormones alter intrinsic brain networks at rest in a woman who underwent brain imaging and venipuncture for 30 consecutive days. Standardized regression analyses illustrate estrogen and progesterone's widespread associations with functional connectivity. Time-lagged analyses examined the temporal directionality of these relationships and suggest that cortical network dynamics (particularly in the Default Mode and Dorsal Attention Networks, whose hubs are densely populated with estrogen receptors) are preceded-and perhaps driven-by hormonal fluctuations. A similar pattern of associations was observed in a follow-up study one year later. Together, these results reveal the rhythmic nature in which brain networks reorganize across the human menstrual cycle. Neuroimaging studies that densely sample the individual connectome have begun to transform our understanding of the brain's functional organization. As these results indicate, taking endocrine factors into account is critical for fully understanding the intrinsic dynamics of the human brain.

Momelotinib (MMB) is a JAK1/2 and ACVR1 inhibitor with demonstrated clinical activity in all 3 hallmarks of myelofibrosis (MF): anemia, constitutional symptoms, and splenomegaly. In this phase 2 open-label translational biology study (NCT02515630) of 41 transfusion-dependent patients with MF, we explored mechanisms underlying the favorable activity of MMB on MF-associated iron-restricted anemia, including its impact on serum hepcidin levels, and markers of iron storage and availability, erythropoiesis, and inflammation. A transfusion-independent response (TI-R), defined as red blood cell transfusion independence (TI) ≥12 weeks at any time on study, occurred in 17 patients (41%; 95% confidence interval [CI], 26%-58%), including 14 patients (34%; 95% CI, 20%-51%) who achieved TI-R by week 24. In addition, 78% of TI nonresponse (TI-NR) patients achieved a ≥50% decrease in transfusion requirement for ≥8 weeks. Adverse events (AEs) were consistent with previous studies of MMB in MF, with cough, diarrhea, and nausea as the most common. Twenty-one patients experienced grade ≥3 AEs, most commonly anemia and neutropenia. Consistent with preclinical data, daily MMB treatment led to an acute and persistent decrease in blood hepcidin associated with increased iron availability and markers of erythropoiesis. Baseline characteristics associated with TI-R were lower inflammation and hepcidin as well as increased markers of erythropoiesis and bone marrow function. Overall, the study demonstrates that MMB treatment decreases hepcidin in conjunction with improving iron metabolism and erythropoiesis, suggesting a mechanistic explanation for the reduced transfusion dependency observed in transfusion-dependent MF patients treated with MMB, thereby addressing the key unmet medical need in the MF population.

Photoreceptors are highly specialized sensory neurons with unique metabolic and physiological requirements. These requirements are partially met by Müller glia and cells of the retinal pigment epithelium (RPE), which provide essential metabolites, phagocytose waste, and control the composition of the surrounding microenvironment. A third vital supporting cell type, the retinal microglia, can provide photoreceptors with neurotrophic support or exacerbate neuroinflammation and hasten neuronal cell death. Understanding the physiological requirements for photoreceptor homeostasis and the factors that drive microglia to best promote photoreceptor survival has important implications for the treatment and prevention of blinding degenerative diseases like retinitis pigmentosa and age-related macular degeneration.

BackgroundLongevity as a phenotype entails living longer than average and typically includes living without chronic age-related diseases. Recently, several common genetic components to longevity have been identified. This study aims to identify additional genetic variants associated with longevity using unique and powerful analyses of pedigrees with a statistical excess of healthy elderly individuals identified in the Utah Population Database (UPDB).MethodsFrom an existing biorepository of Utah pedigrees, six independent cousin pairs were selected from four extended pedigrees that exhibited an excess of healthy elderly individuals; whole exome sequencing (WES) was performed on two elderly individuals from each pedigree who were either first cousins or first cousins once removed. Rare (

The retinal ganglion cell (RGC) competence factor ATOH7 is dynamically expressed during retinal histogenesis. ATOH7 transcription is controlled by a promoter-adjacent primary enhancer and a remote shadow enhancer (SE). Deletion of the ATOH7 human SE causes nonsyndromic congenital retinal nonattachment (NCRNA) disease, characterized by optic nerve aplasia and total blindness. We used genome editing to model NCRNA in mice. Deletion of the murine SE reduces Atoh7 messenger RNA (mRNA) fivefold but does not recapitulate optic nerve loss; however, SEdel/knockout (KO) trans heterozygotes have thin optic nerves. By analyzing Atoh7 mRNA and protein levels, RGC development and survival, and chromatin landscape effects, we show that the SE ensures robust Atoh7 transcriptional output. Combining SE deletion and KO and wild-type alleles in a genotypic series, we determined the amount of Atoh7 needed to produce a normal complement of adult RGCs, and the secondary consequences of graded reductions in Atoh7 dosage. Together, these data reveal the workings of an evolutionary fail-safe, a duplicate enhancer mechanism that is hard-wired in the machinery of vertebrate retinal ganglion cell genesis.

We report national scale estimates of CO2 emissions from fossil-fuel combustion and cement production in the United States based directly on atmospheric observations, using a dual-tracer inverse modeling framework and CO2 and [Formula: see text] measurements obtained primarily from the North American portion of the National Oceanic and Atmospheric Administration's Global Greenhouse Gas Reference Network. The derived US national total for 2010 is 1,653 ± 30 TgC yr-1 with an uncertainty ([Formula: see text]) that takes into account random errors associated with atmospheric transport, atmospheric measurements, and specified prior CO2 and 14C fluxes. The atmosphere-derived estimate is significantly larger ([Formula: see text]) than US national emissions for 2010 from three global inventories widely used for CO2 accounting, even after adjustments for emissions that might be sensed by the atmospheric network, but which are not included in inventory totals. It is also larger ([Formula: see text]) than a similarly adjusted total from the US Environmental Protection Agency (EPA), but overlaps EPA's reported upper 95% confidence limit. In contrast, the atmosphere-derived estimate is within [Formula: see text] of the adjusted 2010 annual total and nine of 12 adjusted monthly totals aggregated from the latest version of the high-resolution, US-specific "Vulcan" emission data product. Derived emissions appear to be robust to a range of assumed prior emissions and other parameters of the inversion framework. While we cannot rule out a possible bias from assumed prior Net Ecosystem Exchange over North America, we show that this can be overcome with additional [Formula: see text] measurements. These results indicate the strong potential for quantification of US emissions and their multiyear trends from atmospheric observations.

People often behave differently when they know they are being watched. Here, we report the first investigation of whether such social presence effects also include brain monitoring technology, and also their impacts on the measured neural activity. We demonstrate that merely informing participants that fMRI has the potential to observe (thought-related) brain activity is sufficient to trigger changes in functional connectivity within and between relevant brain networks that have been previously associated selectively with executive and attentional control as well as self-relevant processing, social cognition, and theory of mind. These results demonstrate that an implied social presence, mediated here by recording brain activity with fMRI, can alter brain functional connectivity. These data provide a new manipulation of social attention, as well as shining light on a methodological hazard for researchers using equipment to monitor brain activity.

INTRODUCTIONWith established applications of next-generation sequencing in inherited diseases and oncology, clinical laboratories are evaluating the use of metagenomics for identification of infectious agents directly from patient samples, to aid in the diagnosis of infections. Metagenomic next-generation sequencing for infectious diseases promises an unbiased approach to detection of microbes that does not depend on growth in culture or the targeting of specific pathogens. However, the issues of contamination, interpretation of results, selection of databases used for analysis, and prediction of antimicrobial susceptibilities from sequencing data remain challenges. In this Point-Counterpoint, Steve Miller and Charles Chiu discuss the pros of using direct metagenomic sequencing, while Kyle Rodino and Melissa Miller argue for the use of caution.

Decisions are often based on memory, but memories are often vague and ambiguous. Therefore, one must establish some standard for how strong a memory must feel before it is accepted as part of one’s past. This standard of evidence, called a decision criterion, should be adapted to the demands of a given situation: Sometimes it is critical to accept only strong memories as legitimate, whereas at other times it is more appropriate to act on the basis of relatively weak memory evidence. The ability to shift between these two standards as circumstances warrant is a critical element of successful decision making. We review recent work examining criterion shifting in recognition memory and argue that the true nature of criterion shifting may be seen only at the individual level: Whereas some people shift their criterion quite adaptively, others do not shift at all.