Last Glacial Maximum pattern effects reduce climate sensitivity estimates.

Here, we show that the Last Glacial Maximum (LGM) provides a stronger constraint on equilibrium climate sensitivity (ECS), the global warming from increasing greenhouse gases, after accounting for temperature patterns. Feedbacks governing ECS depend on spatial patterns of surface temperature ("pattern effects"); hence, using the LGM to constrain future warming requires quantifying how temperature patterns produce different feedbacks during LGM cooling versus modern-day warming. Combining data assimilation reconstructions with atmospheric models, we show that the climate is more sensitive to LGM forcing because ice sheets amplify extratropical cooling where feedbacks are destabilizing. Accounting for LGM pattern effects yields a median modern-day ECS of 2.4°C, 66% range 1.7° to 3.5°C (1.4° to 5.0°C, 5 to 95%), from LGM evidence alone. Combining the LGM with other lines of evidence, the best estimate becomes 2.9°C, 66% range 2.4° to 3.5°C (2.1° to 4.1°C, 5 to 95%), substantially narrowing uncertainty compared to recent assessments.

Climate system asymmetries drive eccentricity pacing of hydroclimate during the early Eocene greenhouse.

The early Eocene Climatic Optimum (EECO) represents the peak of Earth's last sustained greenhouse climate interval. To investigate hydroclimate variability in western North America during the EECO, we developed an orbitally resolved leaf wax δ2H record from one of the most well-dated terrestrial paleoclimate archives, the Green River Formation. Our δ2Hwax results show ∼60‰ variation and evidence for eccentricity and precession forcing. iCESM simulations indicate that changes in the Earth's orbit drive large seasonal variations in precipitation and δ2H of precipitation at our study site, primarily during the summer season. Our findings suggest that the astronomical response in δ2Hwax is attributable to an asymmetrical climate response to the seasonal cycle, a "clipping" of precession forcing, and asymmetric carbon cycle dynamics, which further enhance the influence of eccentricity modulation on the hydrological cycle during the EECO. More broadly, our study provides an explanation for how and why eccentricity emerges as a dominant frequency in climate records from ice-free greenhouse worlds.

Spinal GABAergic disinhibition allows microglial activation mediating the development of nociplastic pain in male mice.

Previously we developed a murine model in which postinjury stimulation of an injured area triggers a transition to a nociplastic pain state manifesting as persistent mechanical hypersensitivity outside of the previously injured area. This hypersensitivity was maintained by sex-specific mechanisms; specifically, activated spinal microglia maintained the hypersensitivity only in males. Here we investigated whether spinal microglia drive the transition from acute injury-induced pain to nociplastic pain in males, and if so, how they are activated by normally innocuous stimulation after peripheral injury. Using intraplantar capsaicin injection as an acute peripheral injury and vibration of the injured paw as postinjury stimulation, we found that inhibition of spinal microglia prevents the vibration-induced transition to a nociplastic pain state. The transition was mediated by the ATP-P2X4 pathway, but not BDNF-TrkB signaling. Intrathecally injected GABA receptor agonists after intraplantar capsaicin injection prevented the vibration-induced transition to a nociplastic pain state. Conversely, in the absence of intraplantar capsaicin injection, intrathecally injected GABA receptor antagonists allowed the vibration stimulation of a normal paw to trigger the transition to a spinal microglia-mediated nociplastic pain state only in males. At the spinal level, TNF-α, IL-1ß, and IL-6, but not prostaglandins, contributed to the maintenance of the nociplastic pain state in males. These results demonstrate that in males, the transition from acute injury-induced pain to nociplastic pain is driven by spinal microglia causing neuroinflammation and that peripheral injury-induced spinal GABAergic disinhibition is pivotal for normally innocuous stimulation to activate spinal microglia.

The PhanSST global database of Phanerozoic sea surface temperature proxy data.

Paleotemperature proxy data form the cornerstone of paleoclimate research and are integral to understanding the evolution of the Earth system across the Phanerozoic Eon. Here, we present PhanSST, a database containing over 150,000 data points from five proxy systems that can be used to estimate past sea surface temperature. The geochemical data have a near-global spatial distribution and temporally span most of the Phanerozoic. Each proxy value is associated with consistent and queryable metadata fields, including information about the location, age, and taxonomy of the organism from which the data derive. To promote transparency and reproducibility, we include all available published data, regardless of interpreted preservation state or vital effects. However, we also provide expert-assigned diagenetic assessments, ecological and environmental flags, and other proxy-specific fields, which facilitate informed and responsible reuse of the database. The data are quality control checked and the foraminiferal taxonomy has been updated. PhanSST will serve as a valuable resource to the paleoclimate community and has myriad applications, including evolutionary, geochemical, diagenetic, and proxy calibration studies.

Spatial patterns of climate change across the Paleocene-Eocene Thermal Maximum.

The Paleocene-Eocene Thermal Maximum (PETM; 56 Ma) is one of our best geological analogs for understanding climate dynamics in a "greenhouse" world. However, proxy data representing the event are only available from select marine and terrestrial sedimentary sequences that are unevenly distributed across Earth's surface, limiting our view of the spatial patterns of climate change. Here, we use paleoclimate data assimilation (DA) to combine climate model and proxy information and create a spatially complete reconstruction of the PETM and the climate state that precedes it ("PETM-DA"). Our data-constrained results support strong polar amplification, which in the absence of an extensive cryosphere, is related to temperature feedbacks and loss of seasonal snow on land. The response of the hydrological cycle to PETM warming consists of a narrowing of the Intertropical Convergence Zone, off-equatorial drying, and an intensification of seasonal monsoons and winter storm tracks. Many of these features are also seen in simulations of future climate change under increasing anthropogenic emissions. Since the PETM-DA yields a spatially complete estimate of surface air temperature, it yields a rigorous estimate of global mean temperature change (5.6 ∘C; 5.4 ∘C to 5.9 ∘C, 95% CI) that can be used to calculate equilibrium climate sensitivity (ECS). We find that PETM ECS was 6.5 ∘C (5.7 ∘C to 7.4 ∘C, 95% CI), which is much higher than the present-day range. This supports the view that climate sensitivity increases substantially when greenhouse gas concentrations are high.

High-fat diet causes mechanical allodynia in the absence of injury or diabetic pathology.

Understanding the interactions between diet, obesity, and diabetes is important to tease out mechanisms in painful pathology. Western diet is rich in fats, producing high amounts of circulating bioactive metabolites. However, no research has assessed how a high-fat diet (HFD) alone may sensitize an individual to non-painful stimuli in the absence of obesity or diabetic pathology. To investigate this, we tested the ability of a HFD to stimulate diet-induced hyperalgesic priming, or diet sensitization in male and female mice. Our results revealed that 8 weeks of HFD did not alter baseline pain sensitivity, but both male and female HFD-fed animals exhibited robust mechanical allodynia when exposed to a subthreshold dose of intraplantar Prostaglandin E2 (PGE2) compared to mice on chow diet. Furthermore, calcium imaging in isolated primary sensory neurons of both sexes revealed HFD induced an increased percentage of capsaicin-responsive neurons compared to their chow counterparts. Immunohistochemistry (IHC) showed a HFD-induced upregulation of ATF3, a neuronal marker of injury, in lumbar dorsal root ganglia (DRG). This suggests that a HFD induces allodynia in the absence of a pre-existing condition or injury via dietary components. With this new understanding of how a HFD can contribute to the onset of pain, we can understand the dissociation behind the comorbidities associated with obesity and diabetes to develop pharmacological interventions to treat them more efficiently.

Northern Hemisphere vegetation change drives a Holocene thermal maximum.

The Holocene thermal maximum, a period of global warmth evident in early to mid-Holocene proxy reconstructions, is controversial. Most model simulations of the Holocene have not reproduced this warming, leading to a disagreement known as the Holocene Temperature Conundrum. Pollen records document the expansion of vegetation in the early and mid-Holocene African Sahara and Northern Hemisphere mid- and high latitudes, which has been overlooked in previous modeling studies. Here, we use time slice simulations of the Community Earth System Model to assess the impact of Northern Hemisphere vegetation change on Holocene annual mean temperatures. Our simulations indicate that expansion of Northern Hemisphere vegetation 9000 and 6000 years ago warms Earth's surface by ~0.8° and 0.7°C, respectively, producing a better match with proxy-based reconstructions. Our results suggest that vegetation change is critical for modeling Holocene temperature evolution and highlight its role in driving a mid-Holocene temperature maximum.

Evaluating opioid analgesic prescribing limits: A narrative review.

PURPOSE: In response to the opioid crisis, opioid analgesic guidelines and prescribing limits have proliferated. The purpose of this narrative review is to examine evidence from studies evaluating the patient or public health impact of federal and state opioid analgesic prescribing guidelines and laws, describe gaps and challenges in current research, and highlight opportunities for improving future research. METHODS: We focused on evidence from a literature review covering 2013 through 2019. We identified 30 studies evaluating opioid analgesic thresholds based on federal policies and guidelines, state laws, and Medicaid state plans that attempt to influence the course of patient care at or when the limit is exceeded (e.g., prior authorization). RESULTS: Most studies evaluated changes in prescribing or dispensing patterns of opioid analgesics, largely finding decreases in prescribing after policy enactment. Fewer studies evaluated patient or public health outcomes beyond changes in prescribing and dispensing patterns; results were infrequently stratified by potentially important sociodemographic and clinical factors. No studies assessed the potential for adverse patient outcomes for which we have emerging evidence of harms. CONCLUSIONS: We describe knowledge gaps and propose opportunities for future research to sufficiently assess the potential impact and unintended consequences of opioid analgesic prescribing laws, regulations, guidelines, and policies.

Globally resolved surface temperatures since the Last Glacial Maximum.

Climate changes across the past 24,000 years provide key insights into Earth system responses to external forcing. Climate model simulations1,2 and proxy data3-8 have independently allowed for study of this crucial interval; however, they have at times yielded disparate conclusions. Here, we leverage both types of information using paleoclimate data assimilation9,10 to produce the first proxy-constrained, full-field reanalysis of surface temperature change spanning the Last Glacial Maximum to present at 200-year resolution. We demonstrate that temperature variability across the past 24 thousand years was linked to two primary climatic mechanisms: radiative forcing from ice sheets and greenhouse gases; and a superposition of changes in the ocean overturning circulation and seasonal insolation. In contrast with previous proxy-based reconstructions6,7 our results show that global mean temperature has slightly but steadily warmed, by ~0.5 °C, since the early Holocene (around 9 thousand years ago). When compared with recent temperature changes11, our reanalysis indicates that both the rate and magnitude of modern warming are unusual relative to the changes of the past 24 thousand years.

Subseafloor Archaea reflect 139 kyrs of paleodepositional changes in the northern Red Sea.

The vertical distribution of subseafloor archaeal communities is thought to be primarily controlled by in situ conditions in sediments such as the availability of electron acceptors and donors, although sharp community shifts have also been observed at lithological boundaries suggesting that at least a subset of vertically stratified Archaea form a long-term genetic record of coinciding environmental conditions that occurred at the time of sediment deposition. To substantiate this possibility, we performed a highly resolved 16S rRNA gene survey of vertically stratified archaeal communities paired with paleo-oceanographic proxies in a sedimentary record from the northern Red Sea spanning the last glacial-interglacial cycle (i.e., marine isotope stages 1-6; MIS1-6). Our results show a strong significant correlation between subseafloor archaeal communities and drastic paleodepositional changes associated with glacial low vs. interglacial high stands (ANOSIM; R = .73; p = .001) and only a moderately strong correlation with lithological changes. Bathyarchaeota, Lokiarchaeota, MBGA, and DHVEG-1 were the most abundant identified archaeal groups. Whether they represented ancient cell lines from the time of deposition or migrated to the specific sedimentary horizons after deposition remains speculative. However, we show that the majority of sedimentary archaeal tetraether membrane lipids were of allochthonous origin and not produced in situ. Slow post-burial growth under energy-limited conditions would explain why the downcore distribution of these dominant archaeal groups still indirectly reflect changes in the paleodepositional environment that prevailed during the analyzed marine isotope stages. In addition, archaea seeded from the overlying water column such as Thaumarchaeota and group II and III Euryarchaeota, which were likely not have been able to subsist after burial, were identified from a lower abundance of preserved sedimentary DNA signatures, and represented direct markers of paleoenvironmental changes in the Red Sea spanning the last six marine isotope stages.

TLR4 Signaling Selectively and Directly Promotes CGRP Release from Vagal Afferents in the Mouse.

There has been a long-standing debate regarding the role of peripheral afferents in mediating rapid-onset anorexia among other responses elicited by peripheral inflammatory insults. Thus, the current study assessed the sufficiency of peripheral afferents expressing toll-like receptor 4 (TLR4) to the initiation of the anorexia caused by peripheral bacterial lipopolysaccharide (LPS). We generated a Tlr4 null (Tlr4LoxTB) mouse in which Tlr4 expression is globally disrupted by a loxP-flanked transcription blocking (TB) cassette. This novel mouse model allowed us to restore the endogenous TLR4 expression in specific cell types. Using Zp3-Cre and Nav1.8-Cre mice, we produced mice that express TLR4 in all cells (Tlr4LoxTB X Zp3-Cre) and in peripheral afferents (Tlr4LoxTB X Nav1.8-Cre), respectively. We validated the Tlr4LoxTB mice, which were phenotypically identical to previously reported global TLR4 knock-out mice. Contrary to our expectations, the administration of LPS did not cause rapid-onset anorexia in mice with Nav1.8-restricted TLR4. The later result prompted us to identify Tlr4-expressing vagal afferents using in situ hybridization (ISH). In vivo, we found that Tlr4 mRNA was primarily enriched in vagal Nav1.8 afferents located in the jugular ganglion that co-expressed calcitonin gene-related peptide (CGRP). In vitro, the application of LPS to cultured Nav1.8-restricted TLR4 afferents was sufficient to stimulate the release of CGRP. In summary, we demonstrated using a new mouse model that vagally-expressed TLR4 is selectively involved in stimulating the release of CGRP but not in causing anorexia.

Past climates inform our future.

As the world warms, there is a profound need to improve projections of climate change. Although the latest Earth system models offer an unprecedented number of features, fundamental uncertainties continue to cloud our view of the future. Past climates provide the only opportunity to observe how the Earth system responds to high carbon dioxide, underlining a fundamental role for paleoclimatology in constraining future climate change. Here, we review the relevancy of paleoclimate information for climate prediction and discuss the prospects for emerging methodologies to further insights gained from past climates. Advances in proxy methods and interpretations pave the way for the use of past climates for model evaluation-a practice that we argue should be widely adopted.

Glacial cooling and climate sensitivity revisited.

The Last Glacial Maximum (LGM), one of the best studied palaeoclimatic intervals, offers an excellent opportunity to investigate how the climate system responds to changes in greenhouse gases and the cryosphere. Previous work has sought to constrain the magnitude and pattern of glacial cooling from palaeothermometers1,2, but the uneven distribution of the proxies, as well as their uncertainties, has challenged the construction of a full-field view of the LGM climate state. Here we combine a large collection of geochemical proxies for sea surface temperature with an isotope-enabled climate model ensemble to produce a field reconstruction of LGM temperatures using data assimilation. The reconstruction is validated with withheld proxies as well as independent ice core and speleothem δ18O measurements. Our assimilated product provides a constraint on global mean LGM cooling of -6.1 degrees Celsius (95 per cent confidence interval: -6.5 to -5.7 degrees Celsius). Given assumptions concerning the radiative forcing of greenhouse gases, ice sheets and mineral dust aerosols, this cooling translates to an equilibrium climate sensitivity of 3.4 degrees Celsius (2.4-4.5 degrees Celsius), a value that is higher than previous LGM-based estimates but consistent with the traditional consensus range of 2-4.5 degrees Celsius3,4.

Publisher Correction: A global database of Holocene paleotemperature records.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Author Correction: A global database of Holocene paleotemperature records.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Emergence of an equatorial mode of climate variability in the Indian Ocean.

Presently, the Indian Ocean (IO) resides in a climate state that prevents strong year-to-year climate variations. This may change under greenhouse warming, but the mechanisms remain uncertain, thus limiting our ability to predict future changes in climate extremes. Using climate model simulations, we uncover the emergence of a mode of climate variability capable of generating unprecedented sea surface temperature and rainfall fluctuations across the IO. This mode, which is inhibited under present-day conditions, becomes active in climate states with a shallow thermocline and vigorous upwelling, consistent with the predictions of continued greenhouse warming. These predictions are supported by modeling and proxy evidence of an active mode during glacial intervals that favored such a state. Because of its impact on hydrological variability, the emergence of such a mode would become a first-order source of climate-related risks for the densely populated IO rim.

Publisher Correction: A global database of Holocene paleotemperature records.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A global database of Holocene paleotemperature records.

A comprehensive database of paleoclimate records is needed to place recent warming into the longer-term context of natural climate variability. We present a global compilation of quality-controlled, published, temperature-sensitive proxy records extending back 12,000 years through the Holocene. Data were compiled from 679 sites where time series cover at least 4000 years, are resolved at sub-millennial scale (median spacing of 400 years or finer) and have at least one age control point every 3000 years, with cut-off values slackened in data-sparse regions. The data derive from lake sediment (51%), marine sediment (31%), peat (11%), glacier ice (3%), and other natural archives. The database contains 1319 records, including 157 from the Southern Hemisphere. The multi-proxy database comprises paleotemperature time series based on ecological assemblages, as well as biophysical and geochemical indicators that reflect mean annual or seasonal temperatures, as encoded in the database. This database can be used to reconstruct the spatiotemporal evolution of Holocene temperature at global to regional scales, and is publicly available in Linked Paleo Data (LiPD) format.

Simulation of Eocene extreme warmth and high climate sensitivity through cloud feedbacks.

The Early Eocene, a period of elevated atmospheric CO2 (>1000 ppmv), is considered an analog for future climate. Previous modeling attempts have been unable to reproduce major features of Eocene climate indicated by proxy data without substantial modification to the model physics. Here, we present simulations using a state-of-the-art climate model forced by proxy-estimated CO2 levels that capture the extreme surface warmth and reduced latitudinal temperature gradient of the Early Eocene and the warming of the Paleocene-Eocene Thermal Maximum. Our simulations exhibit increasing equilibrium climate sensitivity with warming and suggest an Eocene sensitivity of more than 6.6°C, much greater than the present-day value (4.2°C). This higher climate sensitivity is mainly attributable to the shortwave cloud feedback, which is linked primarily to cloud microphysical processes. Our findings highlight the role of small-scale cloud processes in determining large-scale climate changes and suggest a potential increase in climate sensitivity with future warming.

Glacial changes in tropical climate amplified by the Indian Ocean.

The mechanisms driving glacial-interglacial changes in the climate of the Indo-Pacific warm pool are poorly understood. Here, we address this question by combining paleoclimate proxies with model simulations of the Last Glacial Maximum climate. We find evidence of two mechanisms explaining key patterns of ocean cooling and rainfall change interpreted from proxy data. Exposure of the Sahul shelf excites a positive ocean-atmosphere feedback involving a stronger surface temperature gradient along the equatorial Indian Ocean and a weaker Walker circulation-a response explaining the drier/wetter dipole across the basin. Northern Hemisphere cooling by ice sheet albedo drives a monsoonal retreat across Africa and the Arabian Peninsula-a response that triggers a weakening of the Indian monsoon via cooling of the Arabian Sea and associated reductions in moisture supply. These results demonstrate the importance of air-sea interactions in the Indian Ocean, amplifying externally forced climate changes over a large part of the tropics.