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The bed nucleus of the stria terminalis (BNST) plays an emerging role in pain regulation. Pharmacological studies have found that inhibiting corticotropin-releasing factor (CRF) signaling in the BNST can selectively mitigate the sensory and affective-motivational components of pain. However, mechanistic insight on the source of CRF that drives BNST responses to these harmful experiences remains unknown. In the present study, we used a series of genetic approaches to show that CRF in the BNST is engaged in the processing and modulation of pain. We conducted cell-type specific in vivo calcium imaging in CRF-Cre mice and found robust and synchronized recruitment of BNST CRF neurons during acute exposures to noxious heat. Distinct patterns of recruitment were observed by sex, as the magnitude and timing of heat responsive activity in BNST CRF neurons differed for male and female mice. We then used a viral approach in Floxed-CRF mice to selectively reduce CRF expression in the BNST and found it decreased nociceptive sensitivity for both sexes and increased paw attending for females. Together, these findings reveal that CRF in the BNST influences multiple facets of the pain experience to impact the sex-specific expression of pain-related behaviors.

The second messenger cAMP plays multiple critical roles in the control of sperm functions essential for male fertility, including motility. The enzyme soluble adenylyl cyclase (sAC; ADCY10) was shown genetically and pharmacologically to be the essential source of cAMP mediating many of these functions. Male mice and men with genetic deletions of sAC are infertile, and their sperm are progressively immotile. Pharmacologically, delivery of potent and specific sAC inhibitors to male mice renders them temporarily infertile, and their sperm are similarly immotile. Here, we show that males from a second, independently derived mouse sAC knockout line are also infertile with progressively immotile sperm. We use these mouse models to determine optimal conditions for pharmacologically elevating intracellular cAMP to rescue the sAC null motility defect. We show that cell-permeable cAMP analogs, but not forskolin, rescue the motility defects of sAC deficient sperm, and we demonstrate that 8Br-cAMP is an efficient cAMP analog to rescue motility.

Currently, no vaccines are available to prevent rickettsioses, while vector-borne rickettsial infections in humans are on the rise globally. In fact, the insufficient understanding of how pathogenic Rickettsia species circumvent host immune defense mechanisms has significantly hindered the development of more effective therapeutics. Rickettsia species (spp.) are strict obligate intracellular bacteria, some of which are pathogenic in their mammalian host, including humans. One critical feature of these stealthy group of pathogens is their ability to manipulate hostile cytosolic environments to their benefits. Although our understanding of Rickettsia cell biology and pathogenesis is evolving, the mechanisms by which pathogenic Rickettsia spp. evade host innate immune detection remain elusive. Here, we show that disease severity in wild-type (WT) C57BL/6J mice infected with Rickettsia typhi (the etiologic agent of murine typhus) and Rickettsia rickettsii (the etiologic agent of Rocky Mountain spotted fever), but not with the nonpathogenic species Rickettsia montanensis , correlated with levels of bacterial burden as detected in the spleens of mice, as well as the serum concentrations of proinflammatory cytokine interleukin-1α (IL-1α) and, to a lesser extent, IL-1β. Antibody-mediated neutralization of IL-1α confirmed a key role in controlling mortality rates and bacterial burdens of rickettsia-infected WT mice. As macrophages are a primary source of both IL-1α and IL-1β cytokines, we determined the mechanism of the antirickettsial activities using bone marrow-derived macrophages. We found that pathogenic R. typhi and R. rickettsii , but not nonpathogenic R. montanensis , eluded pro-IL-1α induction and benefited predominantly from the reduced IL-1α secretion, via a caspase-11–gasdermin D (Gsdmd)-dependent pathway, to facilitate intracytosolic replication. Adoptive transfer experiments identified that IL-1α secretion by macrophages was critical for controlling rickettsiosis in WT mice. In sum, we identified a previously unappreciated pathway by which pathogenic, unlike nonpathogenic, rickettsiae preferentially target the caspase-11–Gsdmd–IL-1α signaling axis in macrophages, thus supporting their replication within the host. IMPORTANCE Currently, no vaccines are available to prevent rickettsioses, while vector-borne rickettsial infections in humans are on the rise globally. In fact, the insufficient understanding of how pathogenic Rickettsia species circumvent host immune defense mechanisms has significantly hindered the development of more effective therapeutics. Here, we identified a previously unappreciated role for the caspase-11–Gsdmd–IL-1α signaling axis in limiting the replication of pathogenic R. rickettsia and R. typhi species in murine macrophages and wild-type (WT) C57BL/6J mice. Adoptive transfer studies further identified IL-1α-secreting macrophages as critical mediators in controlling rickettsial infection in WT mice. Collectively, these findings provide insight into the potential mechanism of how pathogenic, but not nonpathogenic, Rickettsia spp. benefit from a reduction in the caspase-11–Gsdmd-mediated release of IL-1α to support host colonization.

Seafloor volcanic eruptions are difficult to directly observe due to lengthy eruption cycles and the remote location of mid‐ocean ridges. Volcanic eruptions in 2005–2006 at 9°50′N on the East Pacific Rise have been well documented, but the lava volume and flow extent remain uncertain because of the limited near‐bottom bathymetric data. We present near‐bottom data collected during 19 autonomous underwater vehicle (AUV) Sentry dives at 9°50′N in 2018, 2019, and 2021. The resulting 1 m‐resolution bathymetric grid and 20 cm‐resolution sidescan sonar images cover 115 km2, and span the entire area of the 2005–2006 eruptions, including an 8 km2 pre‐eruption survey collected with AUV ABE in 2001. Pre‐ and post‐eruption surveys, combined with sidescan sonar images and seismo‐acoustic impulsive events recorded during the eruptions, are used to quantify the lava flow extent and to estimate changes in seafloor depth caused by lava emplacement. During the 2005–2006 eruptions, lava flowed up to ∼3 km away from the axial summit trough, covering an area of ∼20.8 km2; ∼50% larger than previously thought. Where pre‐ and post‐eruption surveys overlap, individual flow lobes can be resolved, confirming that lava thickness varies from ∼1 to 10 m, and increases with distance from eruptive fissures. The resulting lava volume estimate indicates that ∼57% of the melt extracted from the axial melt lens probably remained in the subsurface as dikes. These observations provide insights into recharge cycles in the subsurface magma system, and are a baseline for studying future eruptions at the 9°50′N area. Plain Language Summary Volcanism on Earth primarily occurs in the oceans, at ridges where plates spread apart and molten rock intrudes the crust and erupts onto the seafloor. These eruptions frequently repave the seafloor and massively impact deep‐sea ecosystems, but they remain poorly understood because the difficulties of collecting data in the deep ocean. We present meter‐scale mapping of the volcanic system at the East Pacific Rise, 9°50′N, which erupted in 1991–1992 and 2005–2006, and is one of the best‐studied hydrothermal vent areas. Using sonar data collected using underwater robots before and after the 2005–2006 eruptions, we identify the margins of lava flows that paved over the seafloor, and estimate their thickness and volume. Lava flowed as far as 3 km from the mid‐ocean ridge, covering an area similar in size to Manhattan Island, NY. Using depth differencing between pre‐ and post‐eruption surveys, we find that lava flows are, on average, ∼1 m thick, and a total volume of 22.4 ± 7 × 106 m3 erupted. The new, 1 m resolution bathymetric and 0.2 m resolution sidescan data provide a baseline that will be essential to study the next volcanic eruption at EPR 9°50’N, which is likely to happen in the coming few years. Key Points Near‐bottom bathymetric and sidescan sonar data collected by autonomous underwater vehicle Sentry reveal meter‐scale volcanic features at East Pacific Rise Flow margin identification shows that 2005–2006 lava extended over an area that is ∼50% larger than previously mapped Volume of 2005–2006 eruptions was 22.4 ± 7 × 106 m3, while 57% of total volume likely remained in the crust as dikes

Fissures and faults provide insight into how plate separation is accommodated by magmatism and brittle deformation during crustal accretion. Although fissure and fault geometry can be used to quantify the spreading process at mid‐ocean ridges, accurate measurements are rare due to insufficiently detailed mapping data. Here, fissures and faults at the fast‐spreading 9°50′N segment of the East Pacific Rise were mapped using bathymetric data collected at 1‐m horizontal resolution by autonomous underwater vehicle Sentry. Fault dip estimates from the bathymetric data were calibrated using co‐registered near‐bottom imagery and depth transects acquired by remotely operated vehicle Jason. Fissures are classified as either eruptive or non‐eruptive (i.e., cracks). Tectonic strain estimated from corrected fault heaves suggests that faulting plays a negligible role in the plate separation on crust younger than 72 kyr (<4 km from the ridge axis). Pre‐ and post‐eruption surveys show that most fissures were reactivated during the eruptions in 2005–2006. Variable eruptive fissure geometry could be explained by the frequency with which each fissure is reactivated and partially infilled. Fissure swarms and lava plateaus in low‐relief areas >2 km from the ridge are spatially associated with off‐axis lower‐crustal magma lenses identified in multichannel seismic data. Deep, closely spaced fissures overlie a relatively shallow portion of the axial magma lens. The width of on‐axis fissures and inferred subsurface dike geometry imply a ∼9‐year long diking recurrence interval to fully accommodate plate spreading, which is broadly consistent with cycle intervals obtained from estimates of melt extraction rates, eruption volumes, and spreading rate. Plain Language Summary New oceanic crust is created by seafloor spreading at mid‐ocean ridges, where lava erupts as the tectonic plates spread apart. Plate separation is accommodated by a combination of slip along dipping faults and the opening of magma‐filled cracks, called dikes. We present bathymetric and profile mapping data collected from near the seafloor on a volcanically active portion of the East Pacific Rise near 9°50′N. The data show faults and fissures (i.e., open cracks) in remarkable detail, with meter‐scale resolution. A total of 707 fissures and 42 faults were identified and measured, suggesting that the amount of plate separation accommodated by faulting is minimal compared to that by dike intrusion causing open cracks. About one‐third of the fissures mapped are located within the region covered by the most recent eruptions in 2005–2006, and most of these fissures seem to have been reactivated from previous eruptions. Based on measurements of fissure width, we estimate that the interval between diking events is ∼9 years, which agrees with previous independent estimates. The analysis in this study reveals the relative importance of faults and fissures in seafloor spreading, and in the magmatic cycles that continuously re‐pave the ocean floor. Key Points >700 fissures mapped at 1‐m bathymetric resolution at 9°50′N East Pacific Rise, most of which were active during the 2005–2006 eruptions Fault slip and crack opening accommodate <0.3% of plate separation, indicating the dominant role of diking at fast‐spreading ridges Fissures and lava flow located >2 km from the ridge axis are spatially associated with off‐axis lower crustal off‐axis magma lens

The influence and effect of cigarette smoking in sarcoidosis is unclear. Here, we evaluated gene-environment interaction between multiple genetic variants including HLA genes and smoking in sarcoidosis defined by two clinical phenotypes, Löfgren’s syndrome (LS) and patients without Löfgren’s syndrome (non-LS). To quantify smoking effects in sarcoidosis, we performed a gene-environment interaction study in a Swedish population-based case-control study consisting of 3,713 individuals. Cases and controls were classified according to their cigarette smoking status and genotypes by Immunochip platform. Gene-smoking interactions were quantified by an additive interaction model using a logistic regression adjusted by sex, age and first two principal components. The estimated attributable proportion (AP) was used to quantify the interaction effect. Assessment of smoking effects with inclusion of genetic information revealed 53 (in LS) and 34 (in non-LS) SNP-smoking additive interactions at false discovery rate (FDR) below 5%. The lead signals interacting with smoking were rs12132140 (AP = 0.56, 95% CI = 0.22–0.90), p  = 1.28e-03) in FCRL1 for LS and rs61780312 (AP = 0.62, 95% CI = 0.28–0.90), p  = 3e-04) in IL23R for non-LS. We further identified 16 genomic loci (in LS) and 13 (in non-LS) that interact with cigarette smoking. These findings suggest that sarcoidosis risk is modulated by smoking due to genetic susceptibility. Therefore, patients having certain gene variants, are at a higher risk for the disease. Consideration of individual’s genetic predisposition is crucial to quantify effects of smoking in sarcoidosis.

Sarcoidosis associated hypercalcemia (SAHC) is a challenging clinical problem as it can result in severe morbidity. Sunlight exposure and conversion of vitamin D to its active form by macrophages in granulomas have been suggested as possible causes. We aimed to disentangle mechanisms behind SAHC by investigating any associations with season, granuloma burden and lung macrophages. Patients with SAHC were identified from a local cohort. The patients were divided in two groups: mild and severe SAHC. Data on when SAHC occurred, HLA-DRB1 alleles, bronchoalveolar lavage fluid (BALF) macrophages, extrapulmonary manifestations (EPM) and serum angiotensin-converting enzyme (s-ACE) as a marker for granuloma burden were retrieved from medical records. Out of 83 patients with SAHC, severe hypercalcemia was found in 36 patients, 75% of whom presented between May and October ( p  < 0.001). No seasonal variation was observed for patients with mild hypercalcemia. Elevated s-ACE was more common in patients with severe hypercalcemia (84% of patients), compared to 46% in the group with mild hypercalcemia ( p  < 0.001). HLA-DRB1 *04 was more frequent in the group with severe hypercalcemia, compared to the mild group (67% vs. 32%, p  < 0.01). Results support SAHC being associated with sun exposure. Risk factors to be observant of are elevated s-ACE and HLA-DRB1 *04.

Sarcoidosis is a multisystem disease of unknown cause. Löfgren's syndrome (LS) is a characteristic subgroup of sarcoidosis that is associated with a good prognosis in sarcoidosis. However, little is known about its genetic architecture or its broader phenotype, non-LS sarcoidosis. To address the genetic architecture of sarcoidosis phenotypes, LS and non-LS. An association study in a white Swedish cohort of 384 LS, 664 non-LS, and 2,086 control subjects, totaling 3,134 subjects using a fine-mapping genotyping platform was conducted. Replication was performed in four independent cohorts, three of white European descent (Germany, n = 4,975; the Netherlands, n = 613; and Czech Republic, n = 521), and one of black African descent (United States, n = 1,657), totaling 7,766 subjects. A total of 727 LS-associated variants expanding throughout the extended major histocompatibility complex (MHC) region and 68 non-LS-associated variants located in the MHC class II region were identified and confirmed. A shared overlap between LS and non-LS defined by 17 variants located in the MHC class II region was found. Outside the MHC region, two LS-associated loci, in ADCY3 and between CSMD1 and MCPH1, were observed and replicated. Comprehensive and integrative analyses of genetics, transcription, and pathway modeling on LS and non-LS indicates that these sarcoidosis phenotypes have different genetic susceptibility, genomic distributions, and cellular activities, suggesting distinct molecular mechanisms in pathways related to immune response with a common region.

Magnetic anomaly variations near mid‐ocean ridge spreading centers are sensitive to a variety of crustal accretionary processes as well as geomagnetic field variations when the crust forms. We collected near‐bottom vector magnetic anomaly data during a series of 21 autonomous underwater vehicle Sentry dives near 9°50′N on the East Pacific Rise (EPR) covering ∼26 km along‐axis. These data document the 2–3 km wide axial anomaly high that is commonly observed at fast‐spreading ridges but also reveal the presence of a superimposed ∼800 m full wavelength anomaly low. The anomaly low is continuous for ≥13 km along axis and may extend over the entire survey region. A more detailed survey of hydrothermal vents near 9°50.3′N reveals ∼100 m diameter magnetic lows, which are misaligned relative to active vents and therefore cannot explain the continuous axial low. The axial magnetization low persists in magnetic inversions with variable extrusive source thickness, indicating that to the extent to which layer 2A constitutes the sole magnetic source, variations in its thickness alone cannot account for the axial low. Lava accumulation models illustrate that high geomagnetic intensity over the past ∼2.5 kyr, and decreasing intensity over the past ∼900 years, are both consistent with the broad axial anomaly high and the superimposed shorter wavelength low. The continuity of this axial low, and similar features elsewhere on the EPR suggests, that either crustal accretionary processes responsible for this anomaly are common among fast‐spread ridges, or that the observed magnetization low may partially reflect global geomagnetic intensity fluctuations. Plain Language Summary Near‐bottom magnetic anomaly data provide valuable information on crustal accretion processes at mid‐ocean ridges. Using autonomous underwater vehicle data, we analyze near‐bottom magnetic anomalies at the EPR 9°50′N to study crustal accretion at mid‐ocean ridges. We find a continuous axial anomaly low superimposed on the typical broad axial magnetic high, located along the spreading axis covering an along‐axis distance of more than 10 km. This axial anomaly low has been observed at other fast‐spreading mid‐ocean ridges, but the cause of the anomaly low is not well understood. Using magnetic inversion results and numerical models, we consider three possible causes for the axial anomaly low: variations in the thickness of the pillow lavas that are typically modeled as being the primary contributor to the magnetic signal, variations in Earth's geomagnetic field intensity, and hydrothermal vents chemically altering the magnetic minerals in the seafloor basalts. While the global occurrence of the axial anomaly low at other ridges makes it likely that geomagnetic field variations contribute to the low, it is likely that the observed axial magnetic low is caused by a combination of these three factors. Key Points Near‐bottom magnetic data reveal a short‐wavelength low superimposed on the broader axial high along the fast‐spreading East Pacific Rise near 9°50′N Magnetic anomaly data provide insight into crustal accretionary processes and temporal variations in geomagnetic field intensity Vector magnetic anomaly data allows for the analysis of magnetic anomalies independent of uncertainties associated with reduction to the pole

In general, road construction requires the exploitation of large quantities of granular materials, and this generates significant economic and environmental impacts. The use of excavated materials for the construction of fills, embankments and reinforced earth retaining structures is an ideal solution to reduce the exploitation of raw materials. However, the use of excavated materials can be limited when these materials are fine-grained or have low mechanical specifications. In this sense, soils stabilized with quicklime have become a viable alternative for road construction, reducing the use of quarried materials. Although there are standards and techniques for the use of quicklime improved soils for pavements, today the evaluation process of these materials for embankment and fill construction is not well established. This paper presents the results of an investigation to determine the impact of quicklime soil stabilization on the design of embankments and retaining structures reinforced with geosynthetics. First, a road embankment is presented for which a sensitivity analysis was carried out in terms of geometry and volume of material required. Secondly, a mechanically stabilized wall with geosynthetics is presented in which a sensitivity analysis is performed in terms of the amount of geotextile reinforcement required. In both cases, the models were analyzed using the shear strength parameters of a residual soil of the Antioquian batholith in its natural state and stabilized with quicklime obtained in laboratory tests. A quicklime content of 2% and design processes according to Federal Highway Administration (FHWA) manuals were used. The results show that in the embankment a reduction in the volume of material is obtained when using stabilized soil of around 15%, since greater slopes and heights can be used with respect to the geometry of the soil in its natural state. In the case of the stabilized wall, a reduction of approximately 50% in the amount of geosynthetics required was observed, since with the case of stabilized soil it is possible to achieve layer reinforcements of greater thickness and lower strength than those obtained with the soil in its natural state. Both cases show that the implementation of soils stabilized with quicklime can be beneficial in terms of costs since a reduction in resources and materials can be achieved.