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Amish midwife Sarah Mast takes over responsibility from her aging aunt to run the Pleasant Valley birthing center and must fight those skeptical of her abilities, including Aaron Miller, who previously seemed drawn to her.

When animals and their offspring are threatened, parents switch from self-defense to offspring protection. How self-defense is suppressed remains elusive. We postulated that suppression of the self-defense response, freezing, is gated via oxytocin acting in the centro-lateral amygdala (CeL). We found that rat dams conditioned to fear an odor, froze when tested alone, whereas if pups were present, they remained in close contact with them or targeted the threat. Furthermore, blocking oxytocin signaling in the CeL prevented the suppression of maternal freezing. Finally, pups exposed to the odor in the presence of the conditioned dam later froze when re-exposed alone. However, if oxytocin signaling in the dam had been blocked, pups failed to learn. This study provides a functional role for the well-described action of oxytocin in the central amygdala, and demonstrates that self-defense suppression allows for active pup protection and mother-pup interactions crucial for pup threat learning. Animals have many mechanisms to avoid or defend themselves against deadly encounters with predators. However, adult animals frequently put themselves at risk while protecting their more vulnerable offspring from attacks. For example, a killdeerbird with young will fake a broken wing and lead a predator away from its nest. This helps ensure that the parent’s genes live on and contribute to the survival of their species. To do this, the parent must override his or her own defense mechanisms and protect the young instead of themselves. Little is known about the exact mechanisms that allow animals to suppress their own defense mechanisms while protecting their young. Freezing is one tactic that animals will use when they are unable to escape a predator. Previously, studies have shown that the hormone oxytocin, which is produced in the brain, suppresses freezing behavior. Oxytocin plays an important role in birth and breastfeeding, but it is also known to strengthen the bond between individuals, in particular between mother and child. Until now, it was not known whether this hormone also blocks self-defense behaviors in animals protecting their offspring. Now, Rickenbacher et al. show that oxytocin does indeed block freezing behavior, enabling mother rats to protect their offspring in the face of a threatening smell. In the experiments, mother rats were taught to fear the scent of peppermint. Without their young, these rats would freeze whenever they smelled peppermint. Yet, when mother rats with their pups were exposed to the scent, they did not freeze. Instead, they tried to defend their young. Blocking oxytocin in a part of the mothers’ brains called the amygdala, however, caused them to freeze in response to the scent of peppermint, even in the presence of their pups. The experiments show that oxytocin helps mother rats suppress their self-defense mechanisms and is necessary for the mothers to protect their young. Rickenbacher et al. also showed that pups of oxytocin-treated mothers did not learn to freeze in response to the threat. But pups of untreated mothers who defended them, learned to freeze when they were exposed to the scent of peppermint. A next step will be to record neurons that produce oxytocin to better understand how the presence of the pups stimulate its production in their mothers. In addition, it is still unclear how pups learn from their mothers to freeze in response to a threat. One possibility is that the mother produces a molecule that signals danger. Identifying this molecule would be the next step.

ObjectiveThe FOURIER trial showed a benefit of the PCSK9 inhibitor evolocumab over placebo with respect to cardiovascular outcomes in patients with cardiovascular disease. However, we observed some inconsistencies between the information in the Clinical Study Report (CSR) and that in the 2017 primary trial results publication. We aimed to restore the mortality data in the FOURIER trial based on the information contained in the death narratives in the CSR.MethodsMortality data in the primary results publication were compared with that in the CSR. In cases of discrepancy between the sources, an independent committee blindly readjudicated and restored the cause of death according to the information in the CSR narratives.ResultsFor 360/870 deaths (41.4%), the cause of death adjudicated by the FOURIER clinical events committee differed from that declared by the local clinical investigator. When comparing the CSR information with the 2017 primary results publication, we found 11 more deaths from myocardial infarction in the evolocumab group (36 vs 25) and 3 less deaths in the placebo group (27 vs 30, respectively). In the CSR, the number of deaths due to cardiac failure in the evolocumab group was almost double those in the placebo group (31 vs 16). While cardiac and vascular deaths were not assessed as separate outcomes in the original trial analysis, after readjudication, we noted that cardiac deaths were numerically, but non-significantly, higher in the evolocumab group (113) than in the placebo group (88; relative risk (RR) 1.28, 95% CI 0.97 to 1.69, p=0.078), whereas non-cardiac vascular deaths were similar between groups (37 in each; RR 1.00, 95% CI 0.63 to 1.58, p=0.999). The reported HR for cardiovascular mortality in the original trial analysis was 1.05 (95% CI 0.88 to 1.25); after readjudication, we found a greater (although still non-significant) relative increase in cardiovascular mortality in the evolocumab treatment group (RR 1.20, 95% CI 0.95 to 1.51, p=0.13).ConclusionAfter readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm. At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our readjudication. A complete restoration of the FOURIER trial data is required. In the meantime, clinicians should be sceptical about prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.Trial registration numbersNCT01764633.

BackgroundThe first-pass effect (FPE) has emerged as a key metric for efficacy in mechanical thrombectomy (MT). The hyperdense vessel sign (HDVS) on non-contrast head CT (NCCT) indicates a higher clot content of red blood cells.ObjectiveTo assess whether the HDVS could serve as an imaging biomarker for guiding first-line device selection in MT.MethodsA prospective MT database was reviewed for consecutive patients with anterior circulation large vessel occlusion stroke who underwent thrombectomy with stent retriever (SR) or contact aspiration (CA) as first-line therapy between January 2012 and November 2018. Pretreatment NCCT scans were evaluated for the presence of HDVS. The primary outcome was FPE (modified Thrombolysis in Cerebral Infarction score 2c/3). The primary analysis was the interaction between HDVS and thrombectomy modality on FPE. Secondary analyses aimed to evaluate the predictors of FPE.ResultsA total of 779 patients qualified for the analysis. HDVS and FPE were reported in 473 (60.7%) and 286 (36.7%) patients, respectively. The presence of HDVS significantly modified the effect of thrombectomy modality on FPE (p=0.01), with patients with HDVS having a significantly higher rate of FPE with a SR (41.3% vs 22.2%, p=0.001; adjusted OR 2.11 (95% CI 1.20 to 3.70), p=0.009) and non-HDVS patients having a numerically better response to CA (41.4% vs 33.9%, p=0.28; adjusted OR 0.58 (95% CI 0.311 to 1.084), p=0.088). Age (OR 1.01 (95% CI 1.00 to 1.02), p=0.04) and balloon guide catheter (OR 2.08 (95% CI 1.24 to 3.47), p=0.005) were independent predictors of FPE in the overall population.ConclusionOur data suggest that patients with HDVS may have a better response to SRs than CA for the FPE. Larger confirmatory prospective studies are warranted.

The Farm Animal Genotype-Tissue Expression (FarmGTEx) project has been established to develop a public resource of genetic regulatory variants in livestock, which is essential for linking genetic polymorphisms to variation in phenotypes, helping fundamental biological discovery and exploitation in animal breeding and human biomedicine. Here we show results from the pilot phase of PigGTEx by processing 5,457 RNA-sequencing and 1,602 whole-genome sequencing samples passing quality control from pigs. We build a pig genotype imputation panel and associate millions of genetic variants with five types of transcriptomic phenotypes in 34 tissues. We evaluate tissue specificity of regulatory effects and elucidate molecular mechanisms of their action using multi-omics data. Leveraging this resource, we decipher regulatory mechanisms underlying 207 pig complex phenotypes and demonstrate the similarity of pigs to humans in gene expression and the genetic regulation behind complex phenotypes, supporting the importance of pigs as a human biomedical model. The pilot phase of PigGTEx, re-analyzing 5,457 published RNA-seq samples, presents a pan-tissue catalog of molecular quantitative trait loci. Cross-species comparisons identify traits with shared genetic regulation in humans.

Abstract Asymmetries are essential for proper organization and function of organ systems. Genetic studies in bilaterians have shown signaling through the Nodal/Smad2 pathway plays a key, conserved role in the establishment of body asymmetries. Although the main molecular players in the network for the establishment of left-right asymmetry (LRA) have been deeply described in deuterostomes, little is known about the regulation of Nodal signaling in spiralians. Here, we identified orthologs of the egf-cfc gene, a master regulator of the Nodal pathway in vertebrates, in several invertebrate species, which includes the first evidence of its presence in non-deuterostomes. Our functional experiments indicate that despite being present, egf-cfc does not play a role in the establishment of LRA in gastropods. However, experiments in zebrafish suggest that a single amino acid mutation in the egf-cfc gene in at least the common ancestor of chordates was the necessary step to induce a gain of function in LRA regulation. This study shows that the egf-cfc gene likely appeared in the ancestors of deuterostomes and “protostomes”, before being adopted as a mechanism to regulate the Nodal pathway and the establishment of LRA in some lineages of deuterostomes.

Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis (TB), a disease that, although preventable and curable, remains a global epidemic due to the emergence of resistance and a latent form responsible for a long period of treatment. Drug discovery in TB is a challenging task due to the heterogeneity of the disease, the emergence of resistance, and uncomplete knowledge of the pathophysiology of the disease. The limited permeability of the cell wall and the presence of multiple efflux pumps remain a major barrier to achieve effective intracellular drug accumulation. While the complete genome sequence of Mtb has been determined and several potential protein targets have been validated, the lack of adequate models for in vitro and in vivo studies is a limiting factor in TB drug discovery programs. In current therapeutic regimens, less than 0.5% of bacterial proteins are targeted during the biosynthesis of the cell wall and the energetic metabolism of two of the most important processes exploited for TB chemotherapeutics. This review provides an overview on the current challenges in TB drug discovery and emerging Mtb druggable proteins, and explains how chemical probes for protein profiling enabled the identification of new targets and biomarkers, paving the way to disruptive therapeutic regimens and diagnostic tools.

The influence of the gut microbiota on traumatic brain injury (TBI) is presently unknown. This knowledge gap is of paramount clinical significance as TBI patients are highly susceptible to alterations in the gut microbiota by antibiotic exposure. Antibiotic-induced gut microbial dysbiosis established prior to TBI significantly worsened neuronal loss and reduced microglia activation in the injured hippocampus with concomitant changes in fear memory response. Importantly, antibiotic exposure for 1 week after TBI reduced cortical infiltration of Ly6C high monocytes, increased microglial pro-inflammatory markers, and decreased T lymphocyte infiltration, which persisted through 1 month post-injury. Moreover, microbial dysbiosis was associated with reduced neurogenesis in the dentate gyrus 1 week after TBI. By 3 months after injury (11 weeks after discontinuation of the antibiotics), we observed increased microglial proliferation, increased hippocampal neuronal loss, and modulation of fear memory response. These data demonstrate that antibiotic-induced gut microbial dysbiosis after TBI impacts neuroinflammation, neurogenesis, and fear memory and implicate gut microbial modulation as a potential therapeutic intervention for TBI.

BackgroundCarotid webs (CaW) are now recognized as a cause of ischemic stroke in young patients. The thromboembolic potential appears related to the CaW’s morphology and consequent impact on local flow dynamics. We aim to evaluate the reliability of different measurement methods for the quantification of CaW and their relationship to symptomatic status, presence of large vessel occlusion stroke (LVOS), clot burden and final infarct volume.MethodsThis was a retrospective analysis of the local comprehensive stroke center CaW database (September 2014–July 2019). CT angiograms (CTAs) were reviewed independently by two raters, blinded to the clinical information and laterality of the stroke/transient ischemic attack. CaW were quantified with 1-D (length), 2-D (area) and 3-D (volume) measurements via Osirix software. Final infarct volume was calculated on MRI. Patients with superimposed CaW thrombus and no repeat imaging were excluded.ResultsForty-eight CaW (37 symptomatic and 11 contralateral/asymptomatic) in 38 patients were included. Mean age (±SD) was 48.7 (±8.5) years, 78.9% were women and 77.1% were black. Inter-rater agreement was 0.921 (p<0.001) for 1-D, 0.930 (p<0.001) for 2-D, and 0.937 (p<0.001) for 3-D CaW measurements. When comparing symptomatic with asymptomatic CaW, mean web length was 3.2 mm versus 2.5 mm (p<0.02), median area was 5.8 versus 5.0 mm2 (p=0.35) and median volume was 15.0 versus 10.6 mm3 (p<0.04), respectively. CaW with a thinner profile (longer intraluminal projection compared with the base) were more likely to be symptomatic (0.67±0.17 vs 0.88±0.37; p=0.01). Average CaW 1-D and final infarct volume had a weak but positive association (Κ=0.230, p<0.05), while no association among web measurements and the presence of LVOS or clot burden was observed.ConclusionCaW dimension quantification (1-D, 2-D and 3-D) is highly reproducible. Linear and volumetric measurements were more strongly associated with symptoms. The impact of CaW size on the presence of LVOS, clot burden and final infarct volume is unclear.

Cells comprise mechanically active matter that governs their functionality, but intracellular mechanics are difficult to study directly and are poorly understood. However, injected nanodevices open up opportunities to analyse intracellular mechanobiology. Here, we identify a programme of forces and changes to the cytoplasmic mechanical properties required for mouse embryo development from fertilization to the first cell division. Injected, fully internalized nanodevices responded to sperm decondensation and recondensation, and subsequent device behaviour suggested a model for pronuclear convergence based on a gradient of effective cytoplasmic stiffness. The nanodevices reported reduced cytoplasmic mechanical activity during chromosome alignment and indicated that cytoplasmic stiffening occurred during embryo elongation, followed by rapid cytoplasmic softening during cytokinesis (cell division). Forces greater than those inside muscle cells were detected within embryos. These results suggest that intracellular forces are part of a concerted programme that is necessary for development at the origin of a new embryonic life. Mechanical properties and forces sculpt the behaviour of cells in living organisms. Silicon-based nanochips implanted into mouse one-cell embryos have been used to reveal mechanical changes during the early onset of embryonic development.