A screening-level human health risk assessment of dietary intake of pesticide residues in produce as compared to consumer guide recommendations.

Consumers are confronted with conflicting information regarding the safety of specific foods. For example, the Environmental Working Group (EWG) publishes an annual consumer guide in which they rank the pesticide contamination of 46 popular fruits and vegetables, which includes designating the 12 with the greatest pesticide contamination as the "Dirty Dozen," to help consumers reduce exposures to toxic pesticides. However, consumer guides like EWG's only incorporate some hazard assessment principles and do not reflect a dietary risk assessment. Therefore, the purpose of this study is to apply risk assessment techniques to EWG's Dirty Dozen list using a uniform screening-level approach to estimate pesticide exposures for U.S. consumers and to characterize the associated chronic human health risks. The most commonly detected pesticide and its representative residue concentrations were identified for each produce type on the 2022 Dirty Dozen list using the USDA Pesticide Data Program database. Estimates of mean dietary consumption in the U.S. were used to calculate dietary exposure to each pesticide-produce combination for adults and children. Pesticide-specific U.S. EPA dietary health-based guidance values (HBGVs) were then used as benchmarks to evaluate the chronic human health risk of consuming each produce type. Overall, the estimated daily exposure for each pesticide-produce combination was below the corresponding HBGV for all exposure scenarios. The current analysis demonstrates that excessive produce-specific pesticide exposure is unexpected as the amount of produce that would need to be consumed on a chronic basis, even among children, far exceeds typical dietary intake. Future research is necessary to assess acute dietary exposure scenarios and to consider cumulative risk.

Molecular Ratchets and Kinetic Asymmetry: Giving Chemistry Direction.

In recent years ratchet mechanisms have transformed the understanding and design of stochastic molecular systems-biological, chemical and physical-in a move away from the mechanical macroscopic analogies that dominated thinking regarding molecular dynamics in the 1990s and early 2000s (e.g. pistons, springs, etc), to the more scale-relevant concepts that underpin out-of-equilibrium research in the molecular sciences today. Ratcheting has established molecular nanotechnology as a research frontier for energy transduction and metabolism, and has enabled the reverse engineering of biomolecular machinery, delivering insights into how molecules 'walk' and track-based synthesizers operate, how the acceleration of chemical reactions enables energy to be transduced by catalysts, and how dynamic (supra)molecular systems can be driven away from equilibrium. The recognition of molecular ratchet mechanisms in biology, and their invention in synthetic systems, is proving significant in areas as diverse as supramolecular chemistry, systems chemistry, dynamic covalent chemistry, DNA nanotechnology, polymer and materials science, molecular biology, heterogeneous catalysis, endergonic synthesis, and many other branches of chemical science. Put simply, ratchet mechanisms give chemistry direction. Kinetic asymmetry, quantified by the outcome of ratcheting, is the dynamic counterpart of structural asymmetry (i.e. chirality). Given the ubiquity of ratchet mechanisms, it is surely just as fundamentally important.

The Impact of Cannabis Use on Cognition in People with HIV: Evidence of Function-Dependent Effects and Mechanisms from Clinical and Preclinical Studies.

PURPOSE OF REVIEW: Cannabis may have beneficial anti-inflammatory effects in people with HIV (PWH); however, given this population's high burden of persisting neurocognitive impairment (NCI), clinicians are concerned they may be particularly vulnerable to the deleterious effects of cannabis on cognition. Here, we present a systematic scoping review of clinical and preclinical studies evaluating the effects of cannabinoid exposure on cognition in HIV. RECENT FINDINGS: Results revealed little evidence to support a harmful impact of cannabis use on cognition in HIV, with few eligible preclinical data existing. Furthermore, the beneficial/harmful effects of cannabis use observed on cognition were function-dependent and confounded by several factors (e.g., age, frequency of use). Results are discussed alongside potential mechanisms of cannabis effects on cognition in HIV (e.g., anti-inflammatory), and considerations are outlined for screening PWH that may benefit from cannabis interventions. We further highlight the value of accelerating research discoveries in this area by utilizing translatable cross-species tasks to facilitate comparisons across human and animal work.

A Minimalistic Covalent Bond-Forming Chemical Reaction Cycle that Consumes Adenosine Diphosphate.

The development of synthetic active matter requires the ability to design materials capable of harnessing energy from a source to carry out work. Nature achieves this using chemical reaction cycles in which energy released from an exergonic chemical reaction is used to drive biochemical processes. Although many chemically fuelled synthetic reaction cycles that control transient responses, such as self-assembly, have been reported, the generally high complexity of the reported systems hampers a full understanding of how the available chemical energy is actually exploited by these systems. This lack of understanding is a limiting factor in the design of chemically fuelled active matter. Here, we report a minimalistic synthetic responsive reaction cycle in which adenosine diphosphate (ADP) triggers the formation of a catalyst for its own hydrolysis. This establishes an interdependence between the concentrations of the network components resulting in the transient formation of the catalyst. The network is sufficiently simple that all kinetic and thermodynamic parameters governing its behaviour can be characterised, allowing kinetic models to be built that simulate the progress of reactions within the network. While the current network does not enable the ADP-hydrolysis reaction to populate a non-equilibrium composition, these models provide insight into the way the network dissipates energy. Furthermore, essential design principles are revealed for constructing driven systems, in which the network composition is driven away from equilibrium through the consumption of chemical energy.

The p24-family and COPII subunit SEC24C facilitate the clearance of alpha1-antitrypsin Z from the endoplasmic reticulum to lysosomes.

A subpopulation of the alpha-1-antitrypsin misfolding Z mutant (ATZ) is cleared from the endoplasmic reticulum (ER) via an ER-to-lysosome-associated degradation (ERLAD) pathway. Here, we report that the COPII subunit SEC24C and the p24-family of proteins facilitate the clearance of ATZ via ERLAD. In addition to the previously reported ERLAD components calnexin and FAM134B, we discovered that ATZ coimmunoprecipitates with the p24-family members TMP21 and TMED9. This contrasts with wild type alpha1-antitrypsin, which did not coimmunoprecipitate with FAM134B, calnexin or the p24-family members. Live-cell imaging revealed that ATZ and the p24-family members traffic together from the ER to lysosomes. Using chemical inhibitors to block ER exit or autophagy, we demonstrated that p24-family members and ATZ co-accumulate at SEC24C marked ER-exit sites or in ER-derived compartments, respectively. Furthermore, depletion of SEC24C, TMP21, or TMED9 inhibited lysosomal trafficking of ATZ and resulted in the increase of intracellular ATZ levels. Conversely, overexpression of these p24-family members resulted in the reduction of ATZ levels. Intriguingly, the p24-family members coimmunoprecipitate with ATZ, FAM134B, and SEC24C. Thus, we propose a model in which the p24-family functions in an adaptor complex linking SEC24C with the ERLAD machinery for the clearance of ATZ.

Amphetamine increases motivation of humans and mice as measured by breakpoint, but does not affect an Electroencephalographic biomarker.

Translation of drug targets from preclinical studies to clinical trials has been aided by cross-species behavioral tasks, but evidence for brain-based engagement during task performance is still required. Cross-species progressive ratio breakpoint tasks (PRBTs) measure motivation-related behavior and are pharmacologically and clinically sensitive. We recently advanced elevated parietal alpha power as a cross-species electroencephalographic (EEG) biomarker of PRBT engagement. Given that amphetamine increases breakpoint in mice, we tested its effects on breakpoint and parietal alpha power in both humans and mice. Twenty-three healthy participants performed the PRBT with EEG after amphetamine or placebo in a double-blind design. C57BL/6J mice were trained on PRBT with EEG (n = 24) and were treated with amphetamine or vehicle. A second cohort of mice was trained on PRBT without EEG (n = 40) and was treated with amphetamine or vehicle. In humans, amphetamine increased breakpoint. In mice, during concomitant EEG, 1 mg/kg of amphetamine significantly decreased breakpoint. In cohort 2, however, 0.3 mg/kg of amphetamine increased breakpoint consistent with human findings. Increased alpha power was observed in both species as they reached breakpoint, replicating previous findings. Amphetamine did not affect alpha power in either species. Amphetamine increased effort in humans and mice. Consistent with previous reports, elevated parietal alpha power was observed in humans and mice as they performed the PRBT. Amphetamine did not affect this EEG biomarker of effort. Hence, these findings support the pharmacological predictive validity of the PRBT to measure effort in humans and mice and suggest that this EEG biomarker is not directly reflective of amphetamine-induced changes in effort.

A pontomesencephalic PACAPergic pathway underlying panic-like behavioral and somatic symptoms in mice.

Panic disorder is characterized by uncontrollable fear accompanied by somatic symptoms that distinguish it from other anxiety disorders. Neural mechanisms underlying these unique symptoms are not completely understood. Here, we report that the pituitary adenylate cyclase-activating polypeptide (PACAP)-expressing neurons in the lateral parabrachial nucleus projecting to the dorsal raphe are crucial for panic-like behavioral and physiological alterations. These neurons are activated by panicogenic stimuli but inhibited in conditioned fear and anxiogenic conditions. Activating these neurons elicits strong defensive behaviors and rapid cardiorespiratory increase without creating aversive memory, whereas inhibiting them attenuates panic-associated symptoms. Chemogenetic or pharmacological inhibition of downstream PACAP receptor-expressing dorsal raphe neurons abolishes panic-like symptoms. The pontomesencephalic PACAPergic pathway is therefore a likely mediator of panicogenesis, and may be a promising therapeutic target for treating panic disorder.

Ratcheting synthesis.

Synthetic chemistry has traditionally relied on reactions between reactants of high chemical potential and transformations that proceed energetically downhill to either a global or local minimum (thermodynamic or kinetic control). Catalysts can be used to manipulate kinetic control, lowering activation energies to influence reaction outcomes. However, such chemistry is still constrained by the shape of one-dimensional reaction coordinates. Coupling synthesis to an orthogonal energy input can allow ratcheting of chemical reaction outcomes, reminiscent of the ways that molecular machines ratchet random thermal motion to bias conformational dynamics. This fundamentally distinct approach to synthesis allows multi-dimensional potential energy surfaces to be navigated, enabling reaction outcomes that cannot be achieved under conventional kinetic or thermodynamic control. In this Review, we discuss how ratcheted synthesis is ubiquitous throughout biology and consider how chemists might harness ratchet mechanisms to accelerate catalysis, drive chemical reactions uphill and programme complex reaction sequences.

An updated evaluation of reported no-observed adverse effect levels for chrysotile, amosite, and crocidolite asbestos for lung cancer and mesothelioma.

This analysis updates two previous analyses that evaluated the exposure-response relationships for lung cancer and mesothelioma in chrysotile-exposed cohorts. We reviewed recently published studies, as well as updated information from previous studies. Based on the 16 studies considered for chrysotile (<10% amphibole), we identified the "no-observed adverse effect level" (NOAEL) for lung cancer and/or mesothelioma; it should be noted that smoking or previous or concurrent occupational exposure to amphiboles (if it existed) was not controlled for. NOAEL values ranged from 2.3-<11.5 f/cc-years to 1600-3200 f/cc-years for lung cancer and from 100-<400 f/cc-years to 800-1599 f/cc-years for mesothelioma. The range of best-estimate NOAELs was estimated to be 97-175 f/cc-years for lung cancer and 250-379 f/cc-years for mesothelioma. None of the six cohorts of cement or friction product manufacturing workers exhibited an increased risk at any exposure level, while all but one of the six studies of textile workers reported an increased risk at one or more exposure levels. This is likely because friction and cement workers were exposed to much shorter chrysotile fibers. Only eight cases of peritoneal mesothelioma were reported in all studies on predominantly chrysotile-exposed cohorts combined. This analysis also proposed best-estimate amosite and crocidolite NOAELs for mesothelioma derived by the application of relative potency estimates to the best-estimate chrysotile NOAELs for mesothelioma and validated by epidemiology studies with exposure-response information. The best-estimate amosite and crocidolite NOAELs for mesothelioma were 2-5 f/cc-years and 0.6-1 f/cc-years, respectively. The rate of peritoneal mesothelioma in amosite- and crocidolite-exposed cohorts was between approximately 70- to 100-fold and several-hundred-fold higher than in chrysotile-exposed cohorts, respectively. These findings will help characterize potential worker and consumer health risks associated with historical and current chrysotile, amosite, and crocidolite exposures.

Heterogeneity in COVID-19 infection among older persons in South Africa: Evidence from national surveillance data.

Background: The 2021 World Health Organization study on the impact of COVID-19 on older people (≥60 years) in the African region highlighted the difficulties they faced as the virus spread across borders and dominated the way of life. These difficulties included disruptions to both essential health care services and social support, as well as disconnections from family and friends. Among those who contracted COVID-19, the risks of severe illness, complications, and mortality were highest among near-old and older persons. Objective: Recognizing that older persons are a diverse group including younger- and older-aged individuals, a study was conducted to track the epidemic among near-old (50-59 years) and older persons (≥60 years) in South Africa covering the 2 years since the epidemic emerged. Methods: Using a quantitative secondary research approach, data for near-old and older persons were extracted for comparative purposes. COVID-19 surveillance outcomes (confirmed cases, hospitalizations, and deaths) and vaccination data were compiled up to March 5th, 2022. COVID-19 surveillance outcomes were plotted by epidemiological week and epidemic waves to visualize the overall growth and trajectory of the epidemic. Means for each age-group and by COVID-19 waves, together with age-specific rates, were calculated. Results: Average numbers of new COVID-19 confirmed cases and hospitalizations were highest among people aged 50-59- and 60-69-years. However, average age-specific infection rates showed that people aged 50-59 years and ≥80 years were most vulnerable to contracting COVID-19. Age-specific hospitalization and death rates increased, with people aged ≥ 70 years most affected. The number of people vaccinated was slightly higher among people aged 50-59 years before Wave Three and during Wave Four, but higher among people aged ≥ 60 years during Wave Three. The findings suggest that uptake of vaccinations stagnated prior to and during Wave Four for both age groups. Discussion: Health promotion messages and COVID-19 epidemiological surveillance and monitoring are still needed, particularly for older persons living in congregate residential and care facilities. Prompt health-seeking should be encouraged, including testing and diagnosis as well as taking up vaccines and boosters, particularly for high-risk older persons.

Short-active gestational photoperiod reduces effortful choice behavior in mice, partial normalization by d-amphetamine.

RATIONALE: Seasonal birth patterns consistently implicate winter gestation as a risk factor for several psychiatric conditions. We recently demonstrated that short-active (SA; 19:5 light:dark)-i.e., "winter-like"-photoperiod exposure across gestation and early life (E0-P28) induces psychiatrically relevant behavioral abnormalities in adult mice, including reduced immobility in the forced swim test (FST) and effortful amotivation. It is unknown, however, whether these effects were driven primarily by prenatal or postnatal mechanisms, and whether perinatal SA photoperiod would similarly reduce effort expenditure in a task relevant to everyday decision-making. OBJECTIVES AND METHODS: We first tested male and female mice exposed to either gestational (E0-P0) or postnatal (E0-P28) SA photoperiod in the FST to determine whether the previously observed alteration was driven primarily by prenatal versus postnatal photoperiod. We then assessed whether SA gestational photoperiod reduces effortful choice behavior in the cross-species effort-based decision-making task (EBDMT) and whether any such deficit could be remediated by d-amphetamine (0.1 and 0.3 mg/kg, i.p.). RESULTS: Mice exposed to prenatal, but not postnatal, SA photoperiod exhibited reduced FST immobility relative to controls and also demonstrated condition-dependently reduced preference for high-effort/high-reward versus low-effort/low-reward contingencies in the EBDMT. This effortful choice deficit was normalized by 0.1 mg/kg amphetamine. CONCLUSIONS: These data: (1) suggest a greater contribution of gestational versus postnatal light conditions to the behavioral effects of perinatal SA photoperiod; and (2) implicate altered dopamine signaling in the behavioral phenotype of the SA-born mouse and possibly in the etiology of winter gestation-associated cases of psychiatric disease.

I see you: a Chaplain case study on existential distress and transdisciplinary support.

In the setting of major disease progression coupled with active pain, hospitalized patients may become disconnected from their metanarratives and personal grounding. Transdisciplinary palliative care teams are poised to foster patients' connection with their metanarratives by collaborating across areas of expertise to establish goals of care and manage total pain. This case study demonstrates: (1) the unique value of the palliative Chaplain in journeying with the patient through existential distress towards self-discovery, and (2) the role of the palliative chaplain in encouraging a transdisciplinary approach to total pain within a palliative care team.

Interprofessional Interventions to Improve Serious Illness Communication in the Intensive Care Unit: A Scoping Review.

Serious illness communication is fundamental to the provision of quality care for patients in the intensive care unit (ICU). Evidence suggests that including interprofessional team members in such communication is beneficial. This scoping review--conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines-maps existing evidence regarding interprofessional interventions to improve serious illness communication in the ICU. The review yielded 14 studies for inclusion, which were organized by 3 thematic categories of strategies implemented: training curriculum, scheduled meetings, and liaison role. Most used a combination of intervention strategies. Outcome measures varied across the studies but could be broadly categorized as patient/family-focused, provider-focused, or systems-focused. Great heterogeneity between studies exists. More research is needed.

Translational cognitive systems: focus on attention.

Cognitive dysfunction, particularly attentional impairment, is a core feature of many psychiatric disorders, yet is inadequately addressed by current treatments. Development of targeted therapeutics for the remediation of attentional deficits requires knowledge of underlying neurocircuit, cellular, and molecular mechanisms that cannot be directly assayed in the clinic. This level of detail can only be acquired by testing animals in cross-species translatable attentional paradigms, in combination with preclinical neuroscience techniques. The 5-choice continuous performance test (5C-CPT) and rodent continuous performance test (rCPT) represent the current state of the art of preclinical assessment of the most commonly studied subtype of attention: sustained attention, or vigilance. These tasks present animals with continuous streams of target stimuli to which they must respond (attention), in addition to non-target stimuli from which they must withhold responses (behavioral inhibition). The 5C-CPT and rCPT utilize the same measures as gold-standard clinical continuous performance tests and predict clinical efficacy of known pro-attentional drugs. They also engage common brain regions across species, although efforts to definitively establish neurophysiological construct validity are ongoing. The validity of these tasks as translational vigilance assessments enables their use in characterizing the neuropathology underlying attentional deficits of animal models of psychiatric disease, and in determining therapeutic potential of drugs ahead of clinical testing. Here, we briefly review the development and validation of such tests of attentional functioning, as well as the data they have generated pertaining to inattention, disinhibition, and impulsivity in psychiatric disorders.

Using Catalysis to Drive Chemistry Away from Equilibrium: Relating Kinetic Asymmetry, Power Strokes, and the Curtin-Hammett Principle in Brownian Ratchets.

Chemically fueled autonomous molecular machines are catalysis-driven systems governed by Brownian information ratchet mechanisms. One fundamental principle behind their operation is kinetic asymmetry, which quantifies the directionality of molecular motors. However, it is difficult for synthetic chemists to apply this concept to molecular design because kinetic asymmetry is usually introduced in abstract mathematical terms involving experimentally inaccessible parameters. Furthermore, two seemingly contradictory mechanisms have been proposed for chemically driven autonomous molecular machines: Brownian ratchet and power stroke mechanisms. This Perspective addresses both these issues, providing accessible and experimentally useful design principles for catalysis-driven molecular machinery. We relate kinetic asymmetry to the Curtin-Hammett principle using a synthetic rotary motor and a kinesin walker as illustrative examples. Our approach describes these molecular motors in terms of the Brownian ratchet mechanism but pinpoints both chemical gating and power strokes as tunable design elements that can affect kinetic asymmetry. We explain why this approach to kinetic asymmetry is consistent with previous ones and outline conditions where power strokes can be useful design elements. Finally, we discuss the role of information, a concept used with different meanings in the literature. We hope that this Perspective will be accessible to a broad range of chemists, clarifying the parameters that can be usefully controlled in the design and synthesis of molecular machines and related systems. It may also aid a more comprehensive and interdisciplinary understanding of biomolecular machinery.

Integrating Narrative Goals of Care in the Medical Intensive Care Unit: Impact on Educational and Clinical Outcomes.

Background: High-quality goals of care (GOC) communication is fundamental to providing excellent critical care. Objective: Educate medical intensive care unit (MICU) clinicians, design and implement workflows relating to GOC communication, and measure the impact on communication proficiency and rate of GOC documentation. Methods: Guided by Lean Six Sigma principles, an interprofessional team from palliative and critical care tailored a multicomponent intervention-the 3-Act Model communication training and workflow modification-to equip and empower the pulmonary and critical care medicine (PCCM) fellow as the clinical lead for GOC discussions. Fellows' education included in-person narrative reflection, asynchronous online didactic and demonstration videos of the 3-Act Model, online roleplays, and direct observation leading GOC discussions in the ICU. PCCM fellows were objectively evaluated for proficiency using the Goals of Care Assessment Tool. To evaluate the impact of our intervention on documented GOC conversations, we performed a retrospective chart review over two 3-month periods (before and after intervention) when the MICU cared exclusively for critically ill patients with coronavirus disease (COVID-19). Results: All PCCM fellows demonstrated proficiency in GOC communication via online simulated roleplays, as well as in observed bedside GOC communication. Per chart review of patients with a minimum of 7 consecutive days in the MICU, documented GOC conversations were found for 5.55% (2/36) of patients during the preintervention period and for 28.89% (13/45) of patients in the postintervention period. Palliative care consults increased in the pre- versus postintervention period: for all patients, 4.85% versus 14.52% (P < 0.05); for patients age ⩾80 years, 3.54% versus 29.41% (P < 0.05); and for patients with MICU length of stay ⩾7 days, 2.78% versus 24.44% (P < 0.05). Conclusion: Combining 3-Act Model education for PCCM fellows with Lean Six Sigma quality improvement resulted in effective GOC communication training and improved palliative care integration in the ICU.

Evaluation of asbestos exposure resulting from simulated application of spiked talcum powders.

This study characterizes airborne asbestos exposures resulting from the adult application of cosmetic talc body powders spiked with known concentrations of tremolite. Raw talc ores were spiked with 0.005% and 0.1% asbestiform or non-asbestiform tremolite. Personal samples were collected during 16 simulated events, including puff and shaker application and associated clean-up activities. Airborne fiber levels (PCM) were not significantly different for simulations involving talc spiked with asbestiform and non-asbestiform tremolite (p = 0.6104). For application and clean-up of talc spiked with 0.005% asbestiform tremolite, 2 of 24 (8.3%) samples were above the LOD for TEM (0.003 f/cc). For application of talc spiked with 0.1% asbestiform tremolite, 21 of 24 (87.5%) were above the LOD for TEM. The corresponding mean PCME asbestos concentrations were 0.016 f/cc for puff and shaker for samples collected in the first 15 min, 0.002 f/cc for puff and 0.004 f/cc for shaker in the second 15 min, and 0.005 f/cc for puff and 0.013 f/cc for shaker for the full 30 min. Mean PCME concentrations for samples collected during clean-up following application of talc spiked with 0.1% asbestiform tremolite were 0.003 f/cc for samples collected in the first 15 min following puff application, 0.005 f/cc for samples collected in the second 15 min following shaker application, and 0 f/cc for the remaining clean-up samples. Using the EPA's exposure factors, we determined the range of cumulative asbestiform fiber exposures that would result from product use, assuming asbestiform tremolite was present at 0.1%.

Tuning the Force, Speed, and Efficiency of an Autonomous Chemically Fueled Information Ratchet.

Autonomous chemically fueled molecular machines that function through information ratchet mechanisms underpin the nonequilibrium processes that sustain life. These biomolecular motors have evolved to be well-suited to the tasks they perform. Synthetic systems that function through similar mechanisms have recently been developed, and their minimalist structures enable the influence of structural changes on machine performance to be assessed. Here, we probe the effect of changes in the fuel and barrier-forming species on the nonequilibrium operation of a carbodiimide-fueled rotaxane-based information ratchet. We examine the machine's ability to catalyze the fuel-to-waste reaction and harness energy from it to drive directional displacement of the macrocycle. These characteristics are intrinsically linked to the speed, force, power, and efficiency of the ratchet output. We find that, just as for biomolecular motors and macroscopic machinery, optimization of one feature (such as speed) can compromise other features (such as the force that can be generated by the ratchet). Balancing speed, power, efficiency, and directionality will likely prove important when developing artificial molecular motors for particular applications.

A central alarm system that gates multi-sensory innate threat cues to the amygdala.

Perception of threats is essential for survival. Previous findings suggest that parallel pathways independently relay innate threat signals from different sensory modalities to multiple brain areas, such as the midbrain and hypothalamus, for immediate avoidance. Yet little is known about whether and how multi-sensory innate threat cues are integrated and conveyed from each sensory modality to the amygdala, a critical brain area for threat perception and learning. Here, we report that neurons expressing calcitonin gene-related peptide (CGRP) in the parvocellular subparafascicular nucleus in the thalamus and external lateral parabrachial nucleus in the brainstem respond to multi-sensory threat cues from various sensory modalities and relay negative valence to the lateral and central amygdala, respectively. Both CGRP populations and their amygdala projections are required for multi-sensory threat perception and aversive memory formation. The identification of unified innate threat pathways may provide insights into developing therapeutic candidates for innate fear-related disorders.