Metabolic diversity in commensal protists regulates intestinal immunity and trans-kingdom competition.

The microbiota influences intestinal health and physiology, yet the contributions of commensal protists to the gut environment have been largely overlooked. Here, we discover human- and rodent-associated parabasalid protists, revealing substantial diversity and prevalence in nonindustrialized human populations. Genomic and metabolomic analyses of murine parabasalids from the genus Tritrichomonas revealed species-level differences in excretion of the metabolite succinate, which results in distinct small intestinal immune responses. Metabolic differences between Tritrichomonas species also determine their ecological niche within the microbiota. By manipulating dietary fibers and developing in vitro protist culture, we show that different Tritrichomonas species prefer dietary polysaccharides or mucus glycans. These polysaccharide preferences drive trans-kingdom competition with specific commensal bacteria, which affects intestinal immunity in a diet-dependent manner. Our findings reveal unappreciated diversity in commensal parabasalids, elucidate differences in commensal protist metabolism, and suggest how dietary interventions could regulate their impact on gut health.

Spatial multiomics map of trophoblast development in early pregnancy.

The relationship between the human placenta-the extraembryonic organ made by the fetus, and the decidua-the mucosal layer of the uterus, is essential to nurture and protect the fetus during pregnancy. Extravillous trophoblast cells (EVTs) derived from placental villi infiltrate the decidua, transforming the maternal arteries into high-conductance vessels1. Defects in trophoblast invasion and arterial transformation established during early pregnancy underlie common pregnancy disorders such as pre-eclampsia2. Here we have generated a spatially resolved multiomics single-cell atlas of the entire human maternal-fetal interface including the myometrium, which enables us to resolve the full trajectory of trophoblast differentiation. We have used this cellular map to infer the possible transcription factors mediating EVT invasion and show that they are preserved in in vitro models of EVT differentiation from primary trophoblast organoids3,4 and trophoblast stem cells5. We define the transcriptomes of the final cell states of trophoblast invasion: placental bed giant cells (fused multinucleated EVTs) and endovascular EVTs (which form plugs inside the maternal arteries). We predict the cell-cell communication events contributing to trophoblast invasion and placental bed giant cell formation, and model the dual role of interstitial EVTs and endovascular EVTs in mediating arterial transformation during early pregnancy. Together, our data provide a comprehensive analysis of postimplantation trophoblast differentiation that can be used to inform the design of experimental models of the human placenta in early pregnancy.

Ridgecrest aftershocks at Coso suppressed by thermal destressing.

Geothermal and volcanic areas are prone to earthquake triggering1,2. The Coso geothermal field in California lies just north of the surface ruptures driven by the 2019 Ridgecrest earthquake (moment magnitude Mw = 7.1), in an area where changes in coseismic stress should have triggered aftershocks3,4. However, no aftershocks were observed there4. Here we show that 30 years of geothermal heat production at Coso depleted shear stresses within the geothermal reservoir. Thermal contraction of the reservoir initially induced substantial seismicity, as observed in the Coso geothermal reservoir, but subsequently depleted the stress available to drive the aftershocks during the Ridgecrest sequence. This destressing changed the faulting style of the reservoir and impeded aftershock triggering. Although unlikely to have been the case for the Ridgecrest earthquake, such a destressed zone could, in principle, impede the propagation of a large earthquake.

Tuft cells mediate commensal remodeling of the small intestinal antimicrobial landscape.

Succinate produced by the commensal protist Tritrichomonas musculis (T. mu) stimulates chemosensory tuft cells, resulting in intestinal type 2 immunity. Tuft cells express the succinate receptor SUCNR1, yet this receptor does not mediate antihelminth immunity nor alter protist colonization. Here, we report that microbial-derived succinate increases Paneth cell numbers and profoundly alters the antimicrobial peptide (AMP) landscape in the small intestine. Succinate was sufficient to drive this epithelial remodeling, but not in mice lacking tuft cell chemosensory components required to detect this metabolite. Tuft cells respond to succinate by stimulating type 2 immunity, leading to interleukin-13-mediated epithelial and AMP expression changes. Moreover, type 2 immunity decreases the total number of mucosa-associated bacteria and alters the small intestinal microbiota composition. Finally, tuft cells can detect short-term bacterial dysbiosis that leads to a spike in luminal succinate levels and modulate AMP production in response. These findings demonstrate that a single metabolite produced by commensals can markedly shift the intestinal AMP profile and suggest that tuft cells utilize SUCNR1 and succinate sensing to modulate bacterial homeostasis.

Genome-lamina interactions are established de novo in the early mouse embryo.

In mammals, the emergence of totipotency after fertilization involves extensive rearrangements of the spatial positioning of the genome1,2. However, the contribution of spatial genome organization to the regulation of developmental programs is unclear3. Here we generate high-resolution maps of genomic interactions with the nuclear lamina (a filamentous meshwork that lines the inner nuclear membrane) in mouse pre-implantation embryos. We reveal that nuclear organization is not inherited from the maternal germline but is instead established de novo shortly after fertilization. The two parental genomes establish lamina-associated domains (LADs)4 with different features that converge after the 8-cell stage. We find that the mechanism of LAD establishment is unrelated to DNA replication. Instead, we show that paternal LAD formation in zygotes is prevented by ectopic expression of Kdm5b, which suggests that LAD establishment may be dependent on remodelling of H3K4 methylation. Our data suggest a step-wise assembly model whereby early LAD formation precedes consolidation of topologically associating domains.

Reconnection-Powered Fast Radio Transients from Coalescing Neutron Star Binaries.

It is an open question whether and how gravitational wave events involving neutron stars can be preceded by electromagnetic counterparts. This Letter shows that the collision of two neutron stars with magnetic fields well below magnetar-level strengths can produce millisecond fast-radio-burst-like transients. Using global force-free electrodynamics simulations, we identify the coherent emission mechanism that might operate in the common magnetosphere of a binary neutron star system prior to merger. We predict that the emission show have frequencies in the range of 10-20 GHz for magnetic fields of B^{*}=10^{11} G at the surfaces of the stars.

Degeneracy in the Inference of Phase Transitions in the Neutron Star Equation of State from Gravitational Wave Data.

Gravitational wave (GW) detections of binary neutron star inspirals will be crucial for constraining the dense matter equation of state (EOS). We demonstrate a new degeneracy in the mapping from tidal deformability data to the EOS, which occurs for models with strong phase transitions. We find that there exists a new family of EOS with phase transitions that set in at different densities and that predict neutron star radii that differ by up to ∼500 m but that produce nearly identical tidal deformabilities for all neutron star masses. Next-generation GW detectors and advances in nuclear theory may be needed to resolve this degeneracy.

Square waves and Bykov T-points in a delay algebraic model for the Kerr-Gires-Tournois interferometer.

We study theoretically the mechanisms of square wave formation of a vertically emitting micro-cavity operated in the Gires-Tournois regime that contains a Kerr medium and that is subjected to strong time-delayed optical feedback and detuned optical injection. We show that in the limit of large delay, square wave solutions of the time-delayed system can be treated as relative homoclinic solutions of an equation with an advanced argument. Based on this, we use concepts of classical homoclinic bifurcation theory to study different types of square wave solutions. In particular, we unveil the mechanisms behind the collapsed snaking scenario of square waves and explain the formation of complex-shaped multistable square wave solutions through a Bykov T-point. Finally, we relate the position of the T-point to the position of the Maxwell point in the original time-delayed system.

Temporal localized states and square-waves in semiconductor micro-resonators with strong time-delayed feedback.

In this paper, we study the dynamics of a vertically emitting micro-cavity operated in the Gires-Tournois regime that contains a semiconductor quantum-well and that is subjected to strong time-delayed optical feedback and detuned optical injection. Using a first principle time-delay model for the optical response, we disclose sets of multistable dark and bright temporal localized states coexisting on their respective bistable homogeneous backgrounds. In the case of anti-resonant optical feedback, we identify square-waves with a period of twice the round-trip in the external cavity. Finally, we perform a multiple time scale analysis in the good cavity limit. The resulting normal form is in good agreement with the original time-delayed model.

Square-wave generation in vertical external-cavity Kerr-Gires-Tournois interferometers.

We study theoretically the mechanisms of square-wave (SW) formation in vertical external-cavity Kerr-Gires-Tournois interferometers in the presence of anti-resonant injection. We provide simple analytical approximations for their plateau intensities and for the conditions of their emergence. We demonstrate that SWs may appear via a homoclinic snaking scenario, leading to the formation of complex-shaped multistable SW solutions. The resulting SWs can host localized structures and robust bound states.

Improving Sensitivity of Arterial Spin Labeling Perfusion MRI in Alzheimer's Disease Using Transfer Learning of Deep Learning-Based ASL Denoising.

BACKGROUND: Arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI) denoising through deep learning (DL) often faces insufficient training data from patients. One solution is to train DL models using healthy subjects' data which are more widely available and transfer them to patients' data. PURPOSE: To evaluate the transferability of a DL-based ASL MRI denoising method (DLASL). STUDY TYPE: Retrospective. SUBJECTS: Four hundred and twenty-eight subjects (189 females) from three cohorts. FIELD STRENGTH/SEQUENCE: 3 T two-dimensional (2D) echo-planar imaging (EPI)-based pseudo-continuous ASL (PCASL) and 2D EPI-based pulsed ASL (PASL) sequences. ASSESSMENT: DLASL was trained using young healthy adults' PCASL data (Dataset 1: 250/30 subjects as training/validation set) and was directly transferred (DTF) to PCASL data from Dataset 2 (45 subjects test set) of normal controls (NC) and Alzheimer's disease (AD) groups. DLASL was fine-tuned (DLASLFT) and tested on PASL data from Dataset 3 (103 subjects test set) of NC and AD. An existing non-DL method (NonDL) was used for comparison. Cerebral blood flow (CBF) images from ASL MRI were compared between NC and AD to assess characteristic hypoperfusion (lower CBF) patterns in AD. CBF image quality and CBF map sensitivity for detecting hypoperfusion using peak t-value and suprathreshold cluster size are outcome measures. STATISTICAL TESTS: Paired t-test, two-sample t-test, one-way analysis of variance, and Tukey honestly significant difference, and linear mixed-effects models were used. P < 0.05 was considered statistically significant. RESULTS: Mean contrast-to-noise ratio (CNR) of Dataset 2 showed that DTF outperformed NonDL (AD: 3.38 vs. 2.64, NC: 3.80 vs. 3.36). On Dataset 3, DLASLFT outperformed NonDL measured by mean CNR (AD: 2.45 vs. 1.87, NC: 2.54 vs. 2.17) and mean radiologic score (2.86 vs. 2.44). Image quality improvement was significant on both test sets. DTF and DLASLFT improved sensitivity for detecting AD-related hypoperfusion patterns compared with NonDL. DATA CONCLUSION: We demonstrated the DLASL's transferability across different ASL sequences and different populations. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Acute effect of high-intensity interval training exercise on redox status in the ovaries of rats fed a high-fat diet.

This study demonstrates the effect of a single high-intensity interval training (HIIT) session on the redox status of rat ovaries with excess adiposity. Forty Wistar female rats (mean (±s.e.m.) weight 94.40 ± 13.40 g) were divided into two groups and fed either a standard diet (SD) or a high-fat diet (HFD) for 62 days. At the end of this period, the rats were subjected to a single HIIT session and were killed 24 h after exercise. Both groups subjected to exercise (SDex and HFDex) generated a significantly higher antioxidant environment by presenting a higher thiol content, which represents a lower oxidation rate of GSH than their respective controls (SD and HFD). The percentage of morphologically normal primary follicles decreased, whereas that of antral follicles increased, in the SDex group. In addition, the HFD group had a higher percentage of degenerated antral follicles than the SD and SDex groups. Cells immunoreactive for α-smooth muscle actin were seen in the cortical stroma and thecal layer enclosing late secondary and tertiary follicles in all groups. Moreover, heme oxygenase and cytochrome P450 family 19 subfamily A member 1 (Cyp19A1) labelling was seen in all antral follicles. Progesterone concentrations were significantly higher in the HFDex than SDex group. In conclusion, this study indicates that a single session of HIIT may result in an improvement in ovary redox status because of metabolic muscle activity by inducing physiological adaptation after exercise in a paracrine manner.

A novel method for the in vitro assembly of virus-like particles and multimeric proteins.

OBJECTIVE: To develop a method for the efficient assembly of viral or multimeric proteins into virus-like particles (VLP) or other macro structures. RESULTS: Protein monomers were assembled by eliminating calcium ions through precipitation. The model protein, rotavirus VP6, assembled into stable, long nanotubes with better quality than the assemblies obtained directly from cell culture. Nanotube length was directly proportional to the initial concentration of VP6 monomers, in accordance with the classic nucleation theory of capsid assembly. The quality of the obtained assemblies was confirmed when the nanotubes were functionalized with metals, yielding unique nanobiomaterials. Assembly efficiency was improved in comparison with other previously proposed methods. CONCLUSIONS: The novel method presented here is simpler and faster than other reported methods for the assembly and disassembly of viral proteins, a step needed for most applications.

Small RNA profiling in Mycobacterium tuberculosis identifies MrsI as necessary for an anticipatory iron sparing response.

One key to the success of Mycobacterium tuberculosis as a pathogen is its ability to reside in the hostile environment of the human macrophage. Bacteria adapt to stress through a variety of mechanisms, including the use of small regulatory RNAs (sRNAs), which posttranscriptionally regulate bacterial gene expression. However, very little is currently known about mycobacterial sRNA-mediated riboregulation. To date, mycobacterial sRNA discovery has been performed primarily in log-phase growth, and no direct interaction between any mycobacterial sRNA and its targets has been validated. Here, we performed large-scale sRNA discovery and expression profiling in M. tuberculosis during exposure to five pathogenically relevant stresses. From these data, we identified a subset of sRNAs that are highly induced in multiple stress conditions. We focused on one of these sRNAs, ncRv11846, here renamed mycobacterial regulatory sRNA in iron (MrsI). We characterized the regulon of MrsI and showed in mycobacteria that it regulates one of its targets, bfrA, through a direct binding interaction. MrsI mediates an iron-sparing response that is required for optimal survival of M. tuberculosis under iron-limiting conditions. However, MrsI is induced by multiple host-like stressors, which appear to trigger MrsI as part of an anticipatory response to impending iron deprivation in the macrophage environment.

Catabolism of biogenic amines in Pseudomonas species.

Biogenic amines (BAs; 2-phenylethylamine, tyramine, dopamine, epinephrine, norepinephrine, octopamine, histamine, tryptamine, serotonin, agmatine, cadaverine, putrescine, spermidine, spermine and certain aliphatic amines) are widely distributed organic molecules that play basic physiological functions in animals, plants and microorganisms. Pseudomonas species can grow in media containing different BAs as carbon and energy sources, a reason why these bacteria are excellent models for studying such catabolic pathways. In this review, we analyse most of the routes used by different species of Pseudomonas (P. putida, P. aeruginosa, P. entomophila and P. fluorescens) to degrade BAs. Analysis of these pathways has led to the identification of a huge number of genes, catabolic enzymes, transport systems and regulators, as well as to understanding of their hierarchy and functional evolution. Knowledge of these pathways has allowed the design and collection of genetically manipulated microbes useful for eliminating BAs from different sources, highlighting the biotechnological applications of these studies.

Association between hoof lesions and fertility in lactating Jersey cows.

The objectives of this study were to evaluate the association between hoof lesions and fertility in dairy cows. Lactating Jersey cows (n = 1,639) were enrolled at 20 ± 3 d in milk (D20), examined and treated for presence of hoof lesions (HL), and evaluated for body condition score (BCS). Afterward, they were managed according to standard farm procedures, including estrus detection and presynchronization and a 5 d Cosynch-72 protocol for cows that failed to show estrus. Ovaries were scanned at 27 and 41 ± 3 d in milk, and cows with a corpus luteum greater than 20 mm on at least 1 exam were considered cyclic. At 120 ± 3 d in milk (D120), cows were re-examined for HL and BCS. Cows were classified at D20 according to HL status as healthy (n = 1,197) or having HL (n = 429), and according to HL category as healthy (n = 1,197) or having a sole hemorrhage (n = 280), noninfectious HL (sole ulcer, toe ulcer, or white line disease; n = 113), or infectious HL (digital dermatitis and foot rot; n = 36). Cows with HL at D20 had reduced odds of being cyclic (38.3 vs. 51.9%) and a longer interval from calving to first service (58 vs. 51 d) compared with healthy cows. Cows with infectious HL at D20 had reduced odds of pregnancy to first service (16.7 vs. 38.3%) compared with healthy cows. Cows with sole hemorrhage at D20 were more likely to lose pregnancies between d 32 and 64 after the first service postpartum compared with healthy cows (10.5 vs. 5.2%). Cows with sole hemorrhage at D20 had a smaller hazard of pregnancy (67.9 vs. 75.5%) at 150 d in milk and more days open (88 vs. 77d) compared with healthy cows. To assess the relationship between the development of HL and fertility, cows were classified as healthy (no HL at D20 and D120; n = 308), cured (any HL at D20 and no HL at D120; n = 72), new HL (no HL at D20 and any HL at D120; n = 597), and chronic (any HL at D20 and D120; n = 226). Sole hemorrhage accounted for 93% of new HL. The proportions of cows with HL at D20 and D120 were 26.9 and 68.4%, respectively. We found no evidence for a difference in pregnancy hazard at 150 d in milk between cows that remained healthy (n = 308) and cows that developed new HL (n = 597). Hoof lesions at D20, but not new HL, were associated with decreased odds of cyclicity, longer interval from calving to first service postpartum, and reduced pregnancy hazard in Jersey cows. The effect of an HL diagnosis in early lactation and management to reduce chronic HL in dairy cows warrants further investigation.

Chronic kidney disease is associated with low BMD at the hip but not at the spine.

Although chronic kidney disease is associated with other bone disorders, osteoporosis can be found in this context, and it is defined based on bone mineral density (BMD), measured by dual-energy X-ray absorptiometry. As CKD progresses, the percentage of normal BMD decreases, whereas that of osteopenia/osteoporosis increases, mostly due to hip involvement, particularly in patients with reduced renal function. INTRODUCTION: Osteoporosis is a highly prevalent disease in patients with chronic kidney disease (CKD). We investigated the features of bone mineral density (BMD) in patients with assorted kidney diseases and hypothesized that low BMD, as measured by dual-energy X-ray absorptiometry (DXA), would be more prevalent as kidney function decreased and would correlate with biomarkers of mineral and bone disease. METHODS: DXA obtained from January 1, 2008, to December 31, 2017, clinical, demographic, and biochemical data at the time of image acquisition were recorded. Data from 1172 patients were included in this study (81.3% women, 79.9% white, and 8.1% diabetic). RESULTS: Osteopenia and osteoporosis in at least one site (total hip or spine) were found in 32.7% and 20.0% of patients, respectively. As CKD progressed, the percentage of patients with normal BMD decreased, whereas the percentage of osteopenia and osteoporosis increased, which was mostly due to the total hip involvement, particularly in patients with estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. Older age and hyperparathyroidism were independent risk factors for osteopenia/osteoporosis at the total hip; female gender, older age, and higher iCa were independently associated with the risk of osteopenia/osteoporosis at the spine. With eGFR > 90 ml/min as reference, the odds ratios for osteoporosis/osteopenia at the hip were 1.51 (95% CI 1.01-2.24) and 1.91 (95% CI 1.13-3.20) for patients with eGFR 30-60 and 15-30 ml/min/1.73 m2, respectively. No CKD stage was significantly associated with the risk of osteoporosis/osteopenia at the spine. CONCLUSION: Our results highlighted that low BMD in patients with CKD is associated with age and hyperparathyroidism, and affects predominantly the hip.

Signatures of Quark-Hadron Phase Transitions in General-Relativistic Neutron-Star Mergers.

Merging binaries of neutron-stars are not only strong sources of gravitational waves, but also have the potential of revealing states of matter at densities and temperatures not accessible in laboratories. A crucial and long-standing question in this context is whether quarks are deconfined as a result of the dramatic increase in density and temperature following the merger. We present the first fully general-relativistic simulations of merging neutron-stars including quarks at finite temperatures that can be switched off consistently in the equation of state. Within our approach, we can determine clearly what signatures a quark-hadron phase transition would leave in the gravitational-wave signal. We show that if after the merger the conditions are met for a phase transition to take place at several times nuclear saturation density, they would lead to a postmerger signal considerably different from the one expected from the inspiral, that can only probe the hadronic part of the equations of state, and to an anticipated collapse of the merged object. We also show that the phase transition leads to a very hot and dense quark core that, when it collapses to a black hole, produces a ringdown signal different from the hadronic one. Finally, in analogy with what is done in heavy-ion collisions, we use the evolution of the temperature and density in the merger remnant to illustrate the properties of the phase transition in a QCD phase diagram.

A cytochrome P450 monooxygenase gene required for biosynthesis of the trichothecene toxin harzianum A in Trichoderma.

Trichothecenes are sesquiterpene toxins produced by diverse fungi, including some species of Trichoderma that are potential plant disease biocontrol agents. Trichoderma arundinaceum produces the trichothecene harzianum A (HA), which consists of the core trichothecene structure (12,13-epoxytrichothec-9-ene, EPT) with a linear polyketide-derived substituent (octa-2,4,6-trienedioyl) esterified to an oxygen at carbon atom 4. The genes required for biosynthesis of EPT and the eight-carbon polyketide precursor of the octa-2,4,6-trienedioyl substituent, as well as for esterification of the substituent to EPT have been described. However, genes required for conversion of the polyketide (octa-2,4,6-trienoic acid) to octa-2,4,6-trienedioyl-CoA, the immediate precursor of the substituent, have not been described. Here, we identified 91 cytochrome P450 monooxygenase genes in the genome sequence of T. arundinaceum, and provided evidence from gene deletion, complementation, cross-culture feeding, and chemical analyses that one of them (tri23) is required for conversion of octa-2,4,6-trienoic acid to octa-2,4,6-trienedioyl-CoA. The gene was detected in other HA-producing Trichoderma species, but not in species of other fungal genera that produce trichothecenes with an octa-2,4,6-trienoic acid-derived substituent. These findings indicate that tri23 is a trichothecene biosynthetic gene unique to Trichoderma species, which in turn suggests that modification of octa-2,4,6-trienoic acid during trichothecene biosynthesis has evolved independently in some fungi.

Histamine catabolism in Pseudomonas putida U: identification of the genes, catabolic enzymes and regulators.

In this study, the catabolic pathway required for the degradation of the biogenic amine histamine (Hin) was genetically and biochemically characterized in Pseudomonas putida U. The 11 proteins (HinABCDGHFLIJK) that participate in this pathway are encoded by genes belonging to three loci hin1, hin2 and hin3 and by the gene hinK. The enzymes HinABCD catalyze the transport and oxidative deamination of histamine to 4-imidazoleacetic acid (ImAA). This reaction is coupled to those of other well-known enzymatic systems (DadXAR and CoxBA-C) that ensure both the recovery of the pyruvate required for Hin deamination and the genesis of the energy needed for Hin uptake. The proteins HinGHFLKIJ catalyze the sequential transformation of ImAA to fumaric acid via N2 -formylisoasparagine, formylaspartic acid and aspartic acid. The identified Hin pathway encompasses all the genes and proteins (transporters, energizing systems, catabolic enzymes and regulators) needed for the biological degradation of Hin. Our work was facilitated by the design and isolation of genetically engineered strains that degrade Hin or ImAA and of mutants that accumulate Ala, Asp and Hin catabolites. The implications of this research with respect to potential biotechnological applications are discussed.