High Throughput Tomography (HiTT) on EMBL beamline P14 on PETRA III.

Here, high-throughput tomography (HiTT), a fast and versatile phase-contrast imaging platform for life-science samples on the EMBL beamline P14 at DESY in Hamburg, Germany, is presented. A high-photon-flux undulator beamline is used to perform tomographic phase-contrast acquisition in about two minutes which is linked to an automated data processing pipeline that delivers a 3D reconstructed data set less than a minute and a half after the completion of the X-ray scan. Combining this workflow with a sophisticated robotic sample changer enables the streamlined collection and reconstruction of X-ray imaging data from potentially hundreds of samples during a beam-time shift. HiTT permits optimal data collection for many different samples and makes possible the imaging of large sample cohorts thus allowing population studies to be attempted. The successful application of HiTT on various soft tissue samples in both liquid (hydrated and also dehydrated) and paraffin-embedded preparations is demonstrated. Furthermore, the feasibility of HiTT to be used as a targeting tool for volume electron microscopy, as well as using HiTT to study plant morphology, is demonstrated. It is also shown how the high-throughput nature of the work has allowed large numbers of `identical' samples to be imaged to enable statistically relevant sample volumes to be studied.

Extraterrestrial Axion Search with the Breakthrough Listen Galactic Center Survey.

Axion dark matter (DM) may efficiently convert to photons in the magnetospheres of neutron stars (NSs), producing nearly monochromatic radio emission. This process is resonantly triggered when the plasma frequency induced by the underlying charge distribution approximately matches the axion mass. We search for evidence of this process using archival Green Bank Telescope data collected in a survey of the Galactic Center in the C band by the Breakthrough Listen project. While Breakthrough Listen aims to find signatures of extraterrestrial life in the radio band, we show that their high-frequency resolution spectral data of the Galactic Center region is ideal for searching for axion-photon transitions generated by the population of NSs in the inner pc of the Galaxy. We use data-driven models to capture the distributions and properties of NSs in the inner Galaxy and compute the expected radio flux from each NS using state-of-the-art ray tracing simulations. We find no evidence for axion DM and set leading constraints on the axion-photon coupling, excluding values down to the level g_{aγγ}∼10^{-11} GeV^{-1} for DM axions for masses between 15 and 35 µeV.

Search for Axionlike Dark Matter Using Solid-State Nuclear Magnetic Resonance.

We report the results of an experimental search for ultralight axionlike dark matter in the mass range 162-166 neV. The detection scheme of our Cosmic Axion Spin Precession Experiment is based on a precision measurement of ^{207}Pb solid-state nuclear magnetic resonance in a polarized ferroelectric crystal. Axionlike dark matter can exert an oscillating torque on ^{207}Pb nuclear spins via the electric dipole moment coupling g_{d} or via the gradient coupling g_{aNN}. We calibrate the detector and characterize the excitation spectrum and relaxation parameters of the nuclear spin ensemble with pulsed magnetic resonance measurements in a 4.4 T magnetic field. We sweep the magnetic field near this value and search for axionlike dark matter with Compton frequency within a 1 MHz band centered at 39.65 MHz. Our measurements place the upper bounds |g_{d}|<9.5×10^{-4} GeV^{-2} and |g_{aNN}|<2.8×10^{-1} GeV^{-1} (95% confidence level) in this frequency range. The constraint on g_{d} corresponds to an upper bound of 1.0×10^{-21} e cm on the amplitude of oscillations of the neutron electric dipole moment and 4.3×10^{-6} on the amplitude of oscillations of CP-violating θ parameter of quantum chromodynamics. Our results demonstrate the feasibility of using solid-state nuclear magnetic resonance to search for axionlike dark matter in the neV mass range.

Central ANG-(1-7) infusion improves blood pressure regulation in antenatal betamethasone-exposed sheep and reveals sex-dependent effects on oxidative stress.

Fetal exposure to betamethasone (BMX) as a consequence of glucocorticoid administration to women threatening premature delivery may lead to long-term deleterious effects on the cardiovascular system and dysregulation of blood pressure in exposed adults. Indeed, adult offspring of BMX sheep exhibit increased mean arterial pressure (MAP) and attenuated baroreflex sensitivity (BRS) that are associated with lower medullary and cerebrospinal fluid (CSF) angiotensin-(1-7) [(ANG-(1-7)] content. Thus we determined the effects of ANG-(1-7) supplementation in the CSF on MAP, BRS, blood pressure (BPV) and heart rate variability (HRV) in conscious animals. The peptide or artificial CSF (aCSF) was infused continuously into the lateral ventricle (intracerebroventricular) of 4-mo-old male and female BMX sheep for 2 wk. Analysis of data from males and females combined revealed that intracerebroventricular ANG-(1-7) significantly lowered MAP and heart rate and improved BRS as compared with baseline; intracerebroventricular aCSF did not change these indexes. Similar patterns were observed for altered hemodynamics and autonomic function produced by intracerebroventricular ANG-(1-7) in both sexes. Oxidative stress and MAP kinase (MAPK) activation were lower in tissues from the dorsomedial medulla (DMM) of ANG-(1-7)-treated males but were unchanged in the treated females, when assessed at the end of the treatment period. We conclude that in the face of ANG-(1-7) deficiency in CSF and medullary tissue in BMX sheep intracerebroventricular supplementation of ANG-(1-7) lowers MAP and restores the impaired autonomic function to a similar degree in both males and females; however, the attenuation of MAPK and oxidative stress within the DMM was evident only in males. NEW & NOTEWORTHY We demonstrate that intracerebroventricular angiotensin-(1-7) [(ANG-(1-7)] treatment for 2 wk in antenatal betamethasone-exposed sheep provides beneficial effects on blood pressure and autonomic function. The physiological improvements are accompanied by an attenuation of oxidative stress in males but not females. The finding that ANG-(1-7) supplementation lowers blood pressure and restores the impaired autonomic function in a model of fetal programming previously shown to exhibit a deficiency in cerebrospinal fluid and brain tissue illustrates the potential for new therapeutic strategies for reducing cardiovascular dysfunction arising from prenatal events.

Tunable Axion Plasma Haloscopes.

We propose a new strategy for searching for dark matter axions using tunable cryogenic plasmas. Unlike current experiments, which repair the mismatch between axion and photon masses by breaking translational invariance (cavity and dielectric haloscopes), a plasma haloscope enables resonant conversion by matching the axion mass to a plasma frequency. A key advantage is that the plasma frequency is unrelated to the physical size of the device, allowing large conversion volumes. We identify wire metamaterials as a promising candidate plasma, wherein the plasma frequency can be tuned by varying the interwire spacing. For realistic experimental sizes, we estimate competitive sensitivity for axion masses of 35-400 µeV, at least.

Defect generation in TiO2 nanotube anodes via heat treatment in various atmospheres for lithium-ion batteries.

In this paper, ordered TiO2 nanotubes were grown on a Ti substrate via electrochemical anodization and subsequently annealed at 450 °C for 4 h under various atmospheres to create different point defects. Oxygen-deficient environments such as Ar and N2 were used to develop oxygen vacancies, while a water vapor (WV) atmosphere was used to generate titanium vacancies. Computational models by density functional theory predicted that the presence of oxygen vacancies would cause electronic conductivity to increase, while the presence of Ti vacancies could lead to decreased conductivity. The predictions were confirmed by two-point electrical conductivity measurements and Mott-Schottky analysis. Raman spectroscopy was also conducted to confirm the presence of defects. The annealed samples were then evaluated as anodes in lithium-ion batteries. The oxygen-deficient samples had an improvement in capacity by 10% and 25% for Ar- and N2-treated samples, respectively, while the WV-treated sample displayed a capacity increase of 24% compared to the stoichiometric control sample (annealed in O2). Electrochemical impedance spectroscopy studies revealed that the WV-treated sample's increased capacity was a consequence of its higher Li diffusivity. The results suggest that balanced electrical and ionic conductivity in nanostructured metal oxide anodes can be tuned through defect generation using heat treatments in various atmospheres for improved electrochemical properties.

Mid-term safety and efficacy in small intracranial aneurysm coiling: results from TARGET® nano prospective independent core lab adjudicated multicenter registry.

Background: The primary objective is to evaluate the safety and effectiveness of Stryker second generation Target® Nano Coils in the treatment of ruptured and unruptured small (<7 mm) intracranial aneurysms. Methods: The TARGET Registry is a prospective, two-arm study with independent medical event monitoring and core-lab adjudication. This paper describes the second arm of the TARGET registry. Patients with de novo intracranial aneurysms were embolized with 2nd generation TARGET Nano coils in 12 US centers. The primary efficacy outcome was adequate aneurysm occlusion (RR occlusion grade I-II) on follow-up. Primary safety outcome was treatment-related morbidity and mortality. Secondary outcomes included aneurysm packing density immediately post-procedure, immediate adequate occlusion, aneurysm re-access rate, retreatment rate and clinical outcomes using modified ranking scale. A secondary analysis investigated the influence of using Nano-predominant coils (≥2/3 of total coil-length) vs. non-Nano-predominant coils (<2/3 of total length). Results: 150 patients with 155 aneurysms met the inclusion and exclusion criteria. (31%) patients with ruptured and (69%) with unruptured aneurysms were treated using TARGET coils. Median age was 58.8 (SD 12.7), 74.7% were females, and 80% were Caucasians. Mean follow-up was 5.23 (SD 2.27) months. Peri-procedural mortality was seen in 2.0% of patients. Good outcome at discharge (mRS 0-2) was seen in 81.3% of the cohort. The median packing density (SD) was 29.4% (14.9). Mid-term complete/near complete occlusion rate was seen in 96% of aneurysms and complete obliteration was seen in 75.2% of aneurysms. Patients treated predominantly with Nano coils had higher PD (32.6% vs. 26.1%, p < 0.001). There was no significant difference in clinical and angiographic outcomes. The mid-term mRS0-2 was achieved in 106/109 (97.2%) patients. All-cause mortality was 5/115 (4.3%). Conclusion: In the multicenter TARGET Registry, 75.8% of aneurysms achieved mid-term complete occlusion, and 96% achieved complete/near complete occlusion with excellent independent functional outcome.

Thermoneutral Housing Enables Studies of Vertical Transmission of Obesogenic Diet-Driven Metabolic Diseases.

Vertical transmission of obesity is a critical contributor to the unabated obesity pandemic and the associated surge in metabolic diseases. Existing experimental models insufficiently recapitulate "human-like" obesity phenotypes, limiting the discovery of how severe obesity in pregnancy instructs vertical transmission of obesity. Here, via utility of thermoneutral housing and obesogenic diet feeding coupled to syngeneic mating of WT obese female and lean male mice on a C57BL/6 background, we present a tractable, more "human-like" approach to specifically investigate how maternal obesity contributes to offspring health. Using this model, we found that maternal obesity decreased neonatal survival, increased offspring adiposity, and accelerated offspring predisposition to obesity and metabolic disease. We also show that severe maternal obesity was sufficient to skew offspring microbiome and create a proinflammatory gestational environment that correlated with inflammatory changes in the offspring in utero and adulthood. Analysis of a human birth cohort study of mothers with and without obesity and their infants was consistent with mouse study findings of maternal inflammation and offspring weight gain propensity. Together, our results show that dietary induction of obesity in female mice coupled to thermoneutral housing can be used for future mechanistic interrogations of obesity and metabolic disease in pregnancy and vertical transmission of pathogenic traits.

Nonaneurysmal subarachnoid hemorrhage: an update.

Nonaneurysmal subarachnoid hemorrhage (NA-SAH) constitutes a heterogeneous group of patients, both perimesencephalic (PMN-SAH) and non-perimesencephalic (nPMN-SAH). Despite many reports and case series, the etiology of NA-SAH remains uncertain. The differences in clinical course and outcome between PMN-SAH and nPMN-SAH are evident and have to be taken into consideration at the time of admission, as aggressive diagnostic evaluation and management are required for latter patient. In terms of diagnostic evaluation, the most important determination is to differentiate PMN-SAH from nPMN-SAH and aneurysmal SAH. PMN-SAH can be distinguished on CT in the majority of patients, but should be confirmed by a negative cerebral angiography. In addition, Convexal NA-SAH is another important subtype of NA-SAH associated with diverse etiologies and symptoms, although prognosis is generally favorable.

Intentional partial coiling dome protection of complex ruptured cerebral aneurysms prevents acute rebleeding and produces favorable clinical outcomes.

BACKGROUND: The coiling of ruptured cerebral aneurysms protects against acute rebleeding; however, whether partially coiling a ruptured cerebral aneurysm protects against acute rebleeding has never been demonstrated. OBJECTIVE: This study was performed to test our hypothesis that intentional partial coiling of complex ruptured cerebral aneurysms, which are unfavorable for clipping and cannot be completely coiled primarily, prevents acute rebleeding to allow for clinical and neurological recovery until definitive treatment and produces favorable clinical outcomes. METHODS: Data were collected from the prospective databases of three centers. Only subarachnoid hemorrhage patients that were treated with a strategy of intentional partial coiling for dome protection were included. This did not include patients in whom the goal was complete coiling but only subtotal coil occlusion was achieved. RESULTS: Fifteen patients [aged 51 ± 13 years; HH 3-5 (n = 7); Fisher 3-4 (n = 9)] were treated with intentional partial dome protection. Aneurysm size was 12.8 ± 5.4 mm; neck size 4.9 ± 3 mm; 12 anterior circulation. Four intentional partial coilings were performed with balloon assistance. Definitive treatment was performed 92 ± 90 days later, with no case of rebleeding. Definitive treatment was clipping (n = 8), stent-coiling (n = 5), Onyx (n = 1), further coiling (n = 1). Clinical outcome was favorable in 13 cases (GOS 4-5), fair in one (GOS 3), and death in one (GOS 1). CONCLUSIONS: Judicious use of a treatment strategy of intentional partial dome protection for complex aneurysms that are not favorable for clipping and in which complete coiling primarily is not possible may prevent acute rebleeding and produce favorable clinical outcomes.

Immunofluorescence-guided segmentation of three-dimensional features in micro-computed tomography datasets of human lung tissue.

Micro-computed tomography (µCT) provides non-destructive three-dimensional (3D) imaging of soft tissue microstructures. Specific features in µCT images can be identified using correlated two-dimensional (2D) histology images allowing manual segmentation. However, this is very time-consuming and requires specialist knowledge of the tissue and imaging modalities involved. Using a custom-designed µCT system optimized for imaging unstained formalin-fixed paraffin-embedded soft tissues, we imaged human lung tissue at isotropic voxel sizes less than 10 µm. Tissue sections were stained with haematoxylin and eosin or cytokeratin 18 in columnar airway epithelial cells using immunofluorescence (IF), as an exemplar of this workflow. Novel utilization of tissue autofluorescence allowed automatic alignment of 2D microscopy images to the 3D µCT data using scripted co-registration and automated image warping algorithms. Warped IF images, which were accurately aligned with the µCT datasets, allowed 3D segmentation of immunoreactive tissue microstructures in the human lung. Blood vessels were segmented semi-automatically using the co-registered µCT datasets. Correlating 2D IF and 3D µCT data enables accurate identification, localization and segmentation of features in fixed soft lung tissue. Our novel correlative imaging workflow provides faster and more automated 3D segmentation of µCT datasets. This is applicable to the huge range of formalin-fixed paraffin-embedded tissues held in biobanks and archives.

Study of the Pathogen Inactivation Mechanism in Salt-Coated Filters.

As COVID-19 exemplifies, respiratory diseases transmitted through aerosols or droplets are global threats to public health, and respiratory protection measures are essential first lines of infection prevention and control. However, common face masks are single use and can cause cross-infection due to the accumulated infectious pathogens. We developed salt-based formulations to coat membrane fibers to fabricate antimicrobial filters. Here, we report a mechanistic study on salt-induced pathogen inactivation. The salt recrystallization following aerosol exposure was characterized over time on sodium chloride (NaCl), potassium sulfate (K2SO4), and potassium chloride (KCl) powders and coatings, which revealed that NaCl and KCl start to recrystallize within 5 min and K2SO4 within 15 min. The inactivation kinetics observed for the H1N1 influenza virus and Klebsiella pneumoniae matched the salt recrystallization well, which was identified as the main destabilizing mechanism. Additionally, the salt-coated filters were prepared with different methods (with and without a vacuum process), which led to salt coatings with different morphologies for diverse applications. Finally, the salt-coated filters caused a loss of pathogen viability independent of transmission mode (aerosols or droplets), against both DI water and artificial saliva suspensions. Overall, these findings increase our understanding of the salt-recrystallization-based technology to develop highly versatile antimicrobial filters.

Stochastic fluctuations of bosonic dark matter.

Numerous theories extending beyond the standard model of particle physics predict the existence of bosons that could constitute dark matter. In the standard halo model of galactic dark matter, the velocity distribution of the bosonic dark matter field defines a characteristic coherence time τc. Until recently, laboratory experiments searching for bosonic dark matter fields have been in the regime where the measurement time T significantly exceeds τc, so null results have been interpreted by assuming a bosonic field amplitude Φ0 fixed by the average local dark matter density. Here we show that experiments operating in the T ≪ τc regime do not sample the full distribution of bosonic dark matter field amplitudes and therefore it is incorrect to assume a fixed value of Φ0 when inferring constraints. Instead, in order to interpret laboratory measurements (even in the event of a discovery), it is necessary to account for the stochastic nature of such a virialized ultralight field. The constraints inferred from several previous null experiments searching for ultralight bosonic dark matter were overestimated by factors ranging from 3 to 10 depending on experimental details, model assumptions, and choice of inference framework.

Length of stay and total hospital charges of clipping versus coiling for ruptured and unruptured adult cerebral aneurysms in the Nationwide Inpatient Sample database 2002 to 2006.

BACKGROUND AND PURPOSE: We have previously reported the difference in length of stay and hospital charges for patients with cerebral aneurysms treated with either clipping or coiling at our institution. We now report an analysis of the same comparison at a national level conducted using the Nationwide Inpatient Sample database. METHODS: We obtained the Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project, Agency for Healthcare Quality and Research. The Nationwide Inpatient Sample is the largest all-payer inpatient care database in the US and represents approximately 20% of all inpatient admissions to US nonfederal hospitals. Hospitalizations for clipping or coiling of ruptured and unruptured cerebral aneurysms from 2002 to 2006 were identified by cross-matching International Classification of Diseases-9 codes for diagnoses of subarachnoid hemorrhage (430) or unruptured cerebral aneurysm (437.3) with procedure codes for clipping (39.51) or coiling (39.79, 39.72, or 39.52) of cerebral aneurysms. Length of hospital stay and total hospital charges for clipping and coiling were compared using linear mixed models adjusted for the following patient and hospital-specific factors: gender, age, race/ethnicity, admission source and type, median income level in patient's postal code of residence, payer for care, comorbidities, and hospital cerebral aneurysm case volume, bed size, teaching status, rural/urban location, and geographic region. RESULTS: There were 9635 hospitalizations for ruptured aneurysm treatments (6019 clipping, 3616 coiling) and 9399 hospitalizations for unruptured aneurysm treatments (4700 clipping, 4699 coiling). For ruptured aneurysm patients, after adjusting for the effects of patient-specific and hospital-specific factors, clipping compared to coiling was associated with significantly longer length of stay (P<0.0001) and significantly higher total hospital charges (P<0.0001). For unruptured aneurysm patients, clipping compared to coiling was associated with significantly longer length of stay (P<0.0001) and significantly higher total hospital charges (P<0.0001). After adjusting for the effects of hospital-level and patient-level characteristics, clipping as compared to coiling was associated with an average of 1.2-times more days in hospitalization for ruptured patients and was associated with an average of 1.8-times more days in hospitalization for unruptured patients. On average, clipping resulted in $15,325 more in total charge for ruptured patients and resulted in $11,263 more in total charge for unruptured patients after considering all relevant hospital and patient characteristics. CONCLUSIONS: The results of this nationwide analysis differed from the findings of our single institution study. Clipping compared to coiling was associated with significantly longer lengths of stay and significantly higher total hospital charges for both ruptured and unruptured aneurysm patients.

Maternal regulation of inflammatory cues is required for induction of preterm birth.

Infection-driven inflammation in pregnancy is a major cause of spontaneous preterm birth (PTB). Both systemic infection and bacterial ascension through the vagina/cervix to the amniotic cavity are strongly associated with PTB. However, the contribution of maternal or fetal inflammatory responses in the context of systemic or localized models of infection-driven PTB is not well defined. Here, using intraperitoneal or intraamniotic LPS challenge, we examined the necessity and sufficiency of maternal and fetal Toll-like receptor (TLR) 4 signaling in induction of inflammatory vigor and PTB. Both systemic and local LPS challenge promoted induction of inflammatory pathways in uteroplacental tissues and induced PTB. Restriction of TLR4 expression to the maternal compartment was sufficient for induction of LPS-driven PTB in either systemic or intraamniotic challenge models. In contrast, restriction of TLR4 expression to the fetal compartment failed to induce LPS-driven PTB. Vav1-Cre-mediated genetic deletion of TLR4 suggested a critical role for maternal immune cells in inflammation-driven PTB. Further, passive transfer of WT in vitro-derived macrophages and dendritic cells to TLR4-null gravid females was sufficient to induce an inflammatory response and drive PTB. Cumulatively, these findings highlight the critical role for maternal regulation of inflammatory cues in induction of inflammation-driven parturition.

Penetrating intracranial trauma of two minors treated with endovascular technique with the use of temporary balloon occlusion for proximal arterial control.

We present two children treated with endovascular techniques to gain proximal arterial control of the internal carotid and vertebral artery prior to removal of penetrating objects from the skull base. Both siblings (8-month-old and 22-month-old boys) were injured by different sharp objects (knife and scissor) by a guardian. They were transported to the emergency room where vascular control, including coil embolisation and internal carotid balloon occlusion, was performed in the neuroendovascular suite for safe removal of penetrating objects. Both minors recovered and were discharged home without any focal neurological deficits. In two children with scissor and knife stab with intracranial penetration, endovascular technique allowed safe removal of objects and ensured proximal arterial control was maintained to control for possible extravasation of blood on removal from the skull base.

Differential outcomes of TLR2 engagement in inflammation-induced preterm birth.

Preterm birth (PTB) is the leading cause of neonatal mortality worldwide. Infection and inflammation are considered main causes of PTB. Among multiple pathogens, Gram-positive bacteria are commonly linked with induction of PTB. Although activation of innate immune responses, via TLR2 engagement, by Gram-positive bacteria is a likely cause, whether induction of PTB depends on the potency of specific microbial components to induce Toll-like receptor (TLR)2-driven inflammation has not been elucidated. Here, we show that TLR2 activation by synthetic lipopeptides, Pam2Cys, and Pam3Cys specifically, variably influenced inflammation and subsequent induction of PTB. Pam2Cys challenge, compared to Pam3Cys, induced PTB and promoted significantly higher expression of inflammatory cytokines, specifically IL-6 and IFN-ß, both in vivo and in vitro. Notably, antibody-mediated neutralization of IL-6 or genetic deletion of type I IFN receptor (IFNAR) was sufficient to protect from Pam2Cys-driven PTB and to temper excessive proinflammatory cytokine production. Conversely, IFN-ß or IL-6 was not sufficient to promote induction of PTB by Pam3Cys. In summary, our data implies a divergent function of TLR2-activating lipopeptides in the magnitude and type of ligand-driven inflammatory vigor in induction of PTB.

Thermoneutral housing exacerbates nonalcoholic fatty liver disease in mice and allows for sex-independent disease modeling.

Nonalcoholic fatty liver disease (NAFLD), a common prelude to cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide. Defining the molecular mechanisms underlying the pathogenesis of NAFLD has been hampered by a lack of animal models that closely recapitulate the severe end of the disease spectrum in humans, including bridging hepatic fibrosis. Here we demonstrate that a novel experimental model employing thermoneutral housing, as opposed to standard housing, resulted in lower stress-driven production of corticosterone, augmented mouse proinflammatory immune responses and markedly exacerbated high-fat diet (HFD)-induced NAFLD pathogenesis. Disease exacerbation at thermoneutrality was conserved across multiple mouse strains and was associated with augmented intestinal permeability, an altered microbiome and activation of inflammatory pathways that are associated with the disease in humans. Depletion of Gram-negative microbiota, hematopoietic cell deletion of Toll-like receptor 4 (TLR4) and inactivation of the IL-17 axis resulted in altered immune responsiveness and protection from thermoneutral-housing-driven NAFLD amplification. Finally, female mice, typically resistant to HFD-induced obesity and NAFLD, develop full disease characteristics at thermoneutrality. Thus, thermoneutral housing provides a sex-independent model of exacerbated NAFLD in mice and represents a novel approach for interrogation of the cellular and molecular mechanisms underlying disease pathogenesis.

Type I interferons regulate susceptibility to inflammation-induced preterm birth.

Preterm birth (PTB) is a leading worldwide cause of morbidity and mortality in infants. Maternal inflammation induced by microbial infection is a critical predisposing factor for PTB. However, biological processes associated with competency of pathogens, including viruses, to induce PTB or sensitize for secondary bacterial infection-driven PTB are unknown. We show that pathogen/pathogen-associated molecular pattern-driven activation of type I IFN/IFN receptor (IFNAR) was sufficient to prime for systemic and uterine proinflammatory chemokine and cytokine production and induction of PTB. Similarly, treatment with recombinant type I IFNs recapitulated such effects by exacerbating proinflammatory cytokine production and reducing the dose of secondary inflammatory challenge required for induction of PTB. Inflammatory challenge-driven induction of PTB was eliminated by defects in type I IFN, TLR, or IL-6 responsiveness, whereas the sequence of type I IFN sensing by IFNAR on hematopoietic cells was essential for regulation of proinflammatory cytokine production. Importantly, we also show that type I IFN priming effects are conserved from mice to nonhuman primates and humans, and expression of both type I IFNs and proinflammatory cytokines is upregulated in human PTB. Thus, activation of the type I IFN/IFNAR axis in pregnancy primes for inflammation-driven PTB and provides an actionable biomarker and therapeutic target for mitigating PTB risk.

Erratum: Thermoneutral housing exacerbates nonalcoholic fatty liver disease in mice and allows for sex-independent disease modeling.

This corrects the article DOI: 10.1038/nm.4346.