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Growing evidence suggests that the gut microbiome (GM) plays a critical role in health and disease. However, the contribution of GM to psychiatric disorders, especially anxiety, remains unclear. We used the Collaborative Cross (CC) mouse population-based model to identify anxiety associated host genetic and GM factors. Anxiety-like behavior of 445 mice across 30 CC strains was measured using the light/dark box assay and documented by video. A custom tracking system was developed to quantify seven anxiety-related phenotypes based on video. Mice were assigned to a low or high anxiety group by consensus clustering using seven anxiety-related phenotypes. Genome-wide association analysis (GWAS) identified 141 genes (264 SNPs) significantly enriched for anxiety and depression related functions. In the same CC cohort, we measured GM composition and identified five families that differ between high and low anxiety mice. Anxiety level was predicted with 79% accuracy and an AUC of 0.81. Mediation analyses revealed that the genetic contribution to anxiety was partially mediated by the GM. Our findings indicate that GM partially mediates and coordinates the effects of genetics on anxiety.

Background The previously published “Dose Response Multicentre International Collaborative Initiative (DoReMi)” study concluded that the high mortality of critically ill patients with acute kidney injury (AKI) was unlikely to be related to an inadequate dose of renal replacement therapy (RRT) and other factors were contributing. This follow-up study aimed to investigate the impact of daily fluid balance and fluid accumulation on mortality of critically ill patients without AKI (N-AKI), with AKI (AKI) and with AKI on RRT (AKI-RRT) receiving an adequate dose of RRT. Methods We prospectively enrolled all consecutive patients admitted to 21 intensive care units (ICUs) from nine countries and collected baseline characteristics, comorbidities, severity of illness, presence of sepsis, daily physiologic parameters and fluid intake-output, AKI stage, need for RRT and survival status. Daily fluid balance was computed and fluid overload (FO) was defined as percentage of admission body weight (BW). Maximum fluid overload (MFO) was the peak value of FO. Results We analysed 1734 patients. A total of 991 (57 %) had N-AKI, 560 (32 %) had AKI but did not have RRT and 183 (11 %) had AKI-RRT. ICU mortality was 22.3 % in AKI patients and 5.6 % in those without AKI ( p  < 0.0001). Progressive fluid accumulation was seen in all three groups. Maximum fluid accumulation occurred on day 2 in N-AKI patients (2.8 % of BW), on day 3 in AKI patients not receiving RRT (4.3 % of BW) and on day 5 in AKI-RRT patients (7.9 % of BW). The main findings were: (1) the odds ratio (OR) for hospital mortality increased by 1.075 (95 % confidence interval 1.055–1.095) with every 1 % increase of MFO. When adjusting for severity of illness and AKI status, the OR changed to 1.044. This phenomenon was a continuum and independent of thresholds as previously reported. (2) Multivariate analysis confirmed that the speed of fluid accumulation was independently associated with ICU mortality. (3) Fluid accumulation increased significantly in the 3-day period prior to the diagnosis of AKI and peaked 3 days later. Conclusions In critically ill patients, the severity and speed of fluid accumulation are independent risk factors for ICU mortality. Fluid balance abnormality precedes and follows the diagnosis of AKI.

With the wide application of quadrotor unmanned aerial vehicles (UAVs), the requirements for their safety and reliability are becoming increasingly stringent. In this paper, based on the feedback of airframe performance health perception information and the predictive function control strategy, the autonomous maintenance of a quadrotor UAV with multi-actuator degradation is realised. Autonomous maintenance architecture is constructed by the predictive maintenance (PdM) idea and the Laguerre function model predictive pontrol (LF-MPC) strategy. Using the two-stage Kalman filter (TSKF) method, based on the established UAV degradation model, the aircraft state and actuator degradation state are predicted simultaneously. For the predictive perception of system health, on the one hand, the system health degree (HD) based on Mahalanobis distance is defined by the degree of airframe state deviation from the expected state, and then the failure threshold of the UAV is obtained. On the other hand, according to the degradation state of each actuator, a comprehensive degradation variable fused with different weight coefficients of multiple actuators degradation is used to obtain the probability density function (PDF) of remaining useful life (RUL) prediction. For the autonomous maintenance of system health, the LF-MPC weight matrixes are adjusted adaptively in real-time based on the HD evaluation, to achieve a compromise balance between UAV performance and control effect, and greatly extend the working time of UAV. Simulation results verified the effectiveness of the proposed method.

The control of complex oxide heterostructures at atomic level generates a rich spectrum of exotic properties and unexpected states at the interface between two separately prepared materials. The frustration of magnetization and conductivity of manganite perovskite at surface/interface which is inimical to their device applications, could also flourish in tailored functionalities in return. Here we prove that the exchange bias (EB) effect can unexpectedly emerge in a (La,Sr)MnO 3 (LSMO) “single” film when large compressive stress imposed through a lattice mismatched substrate. The intrinsic EB behavior is directly demonstrated to be originating from the exchange coupling between ferromagnetic LSMO and an unprecedented LaSrMnO 4 -based spin glass, formed under a large interfacial strain and subsequent self-assembly. The present results not only provide a strategy for producing a new class of delicately functional interface by strain engineering, but also shed promising light on fabricating the EB part of spintronic devices in a single step.

The epidermal growth factor receptor (EGFR) and Notch signaling pathways have antagonistic roles during epidermal differentiation and carcinogenesis. The molecular mechanisms regulating the crosstalk between EGFR and Notch during epidermal transformation are largely unknown. We found enhanced EGFR-dependent signaling, proliferation and oncogenic transformation caused by loss of presenilins (PS), the catalytic components of γ-secretase that generates the Notch1 intracellular domain (NICD). The underlying mechanism for abnormal EGFR signaling in PS-deficient cells involves γ-secretase-independent transcriptional upregulation of the E3 ubiquitin ligase Fbw7. Fbw7α, which targets NICD for degradation, regulates positively EGFR by affecting a proteasome-dependent ubiquitination step essential for constitutive degradation and stability of EGFR. To investigate the pathological relevance of this findings in vivo , we generated a novel epidermal conditional PS-deficient (ePS cDKO) mouse by deleting both PS in keratinocytes of the basal layer of the epidermis. The ePS cDKO mice develop epidermal hyperplasia associated with enhanced expression of both EGFR and Fbw7 and reduced NICD levels in keratinocytes. These findings establish a novel role for PS on epidermal growth and transformation by reciprocally regulating the EGFR and Notch signaling pathways through Fbw7.

A genome-wide screen for genetic alterations in radiation-induced thymic lymphomas generated from p53 +/− and p53 −/− mice showed frequent loss of heterozygosity (LOH) on chromosome 6. Fine mapping of these LOH regions revealed three non-overlapping regions, one of which was refined to a 0.2 Mb interval that contained only the gene encoding homeobox-interacting protein kinase 2 ( Hipk2 ). More than 30% of radiation-induced tumors from both p53 +/− and p53 −/− mice showed heterozygous loss of one Hipk2 allele. Mice carrying a single inactive allele of Hipk2 in the germline were susceptible to induction of tumors by γ-radiation, but most tumors retained and expressed the wild-type allele, suggesting that Hipk2 is a haploinsufficient tumor suppressor gene for mouse lymphoma development. Heterozygous loss of both Hipk2 and p53 confers strong sensitization to radiation-induced lymphoma. We conclude that Hipk2 is a haploinsufficient lymphoma suppressor gene.

With the recent realization of hybrid improper ferroelectricity and room-temperature multiferroic by tilt engineering, “functional” octahedral tilting has become a novel concept in multifunctional perovskite oxides, showing great potential for property manipulation and device design. However, the control of magnetism by octahedral tilting has remained a challenging issue. Here a qualitative and quantitative tilt engineering of exchange coupling, one of the magnetic properties, is demonstrated at compensated G -type antiferromagnetic/ferromagnetic (SrMnO 3 /La 2/3 Sr 1/3 MnO 3 ) interfaces. According to interfacial Hamiltonian, exchange bias (EB) in this system originates from an in-plane antiphase rotation ( a − ) in G -type antiferromagnetic layer. Based on first-principles calculation, tilt patterns in SrMnO 3 are artificially designed in experiment with different epitaxial strain and a much stronger EB is attained in the tensile heterostructure than the compressive counterpart. By controlling the magnitude of octahedral tilting, the manipulation of exchange coupling is even performed in a quantitative manner, as expected in the theoretical estimation. This work realized the combination of tilt engineering and exchange coupling, which might be significant for the development of multifunctional materials and antiferromagnetic spintronics.

There is a gap between the initial formation of cells carrying radiation-induced genetic damage and their contribution to cancer development. Herein, we reveal a previously uncharacterized gene FATS through a genome-wide approach and demonstrate its essential role in regulating the abundance of p21 in surveillance of genome integrity. A large exon coding the NH2-terminal domain of FATS, deleted in spontaneous mouse lymphomas, is much more frequently deleted in radiation-induced mouse lymphomas. Its human counterpart is a fragile site gene at a previously identified loss of heterozygosity site. FATS is essential for maintaining steady-state level of p21 protein and sustaining DNA damage checkpoint. Furthermore, the NH2-terminal FATS physically interacts with histone deacetylase 1 (HDAC1) to enhance the acetylation of endogenous p21, leading to the stabilization of p21. Our results reveal a molecular linkage between p21 abundance and radiation-induced carcinogenesis.

Summary Fibroblast growth factor 23(FGF23) is a bone-derived hormone which regulates mineral homeostasis but may also have a role in cardiovascular disease. Here, we found that higher plasma FGF23 was independently associated with decreased heart rate variability in stage 5 CKD patients and parathyroidectomy may reverse these abnormal indicators. Introduction Lower heart rate variability (HRV) in patients with chronic kidney disease (CKD) compared with healthy controls is associated with increased risk of cardiovascular disease (CVD). Higher levels of plasma FGF23 also predict higher risk of CVD. Here, we aimed to evaluate the relationship between plasma FGF23 levels and HRV in patients with stage 5 CKD and to investigate longitudinal changes of them together with the correlation between their changes in two severe secondary hyperparathyroidism (SHPT) subgroups with successful parathyroidectomy (PTX) and persistent SHPT. Methods This cross-sectional study included 100 stage 5 CKD patients, 78 controls, and a prospective study in two PTX subgroups classified as successful PTX ( n  = 24) and persistent SHPT ( n  = 4) follow-up. Blood examination and 24-h Holter monitoring for HRV were measured. Results Most HRV indices were lower in stage 5 CKD patients than in healthy controls, and plasma FGF23 levels were higher. In multivariate stepwise regression models, levels of plasma FGF23 and serum parathyroid hormone (PTH) were correlated with HRV. The successful PTX subgroup had significant improvements over baseline in HRV indices. Persistent SHPT subgroup had numerically similar changes in HRV indices. However, plasma FGF23 levels decreased in both subgroups. Conclusions Plasma FGF23 levels were higher in CKD patients than in controls, much higher in patients with severe SHPT. FGF23 was independently associated with decreased HRV in stage 5 CKD. Successful PTX may reverse these abnormal indicators and contribute to decreases in the risk of cardiovascular disease.

Purpose Primary insomnia is a persistent and recurrent disorder as well as a risk factor for depression. The aim of this study was to determine whether the zolpidem combined with paroxetine would be effective in the treatment of patients with primary insomnia. Methods Ninety patients meeting DSM-IV criteria for primary insomnia were randomly assigned to 8 weeks of treatment with zolpidem combined with paroxetine (the combined treatment group, n  = 45) or zolpidem combined with placebo (the control group, n  = 45). Patients were assessed with the Pittsburgh Sleep Quality Index (PSQI), polysomnography (PSG), and the Treatment Emergent Symptom Scale (TESS). Results Compared with the control group, the combined treatment group was more significantly improved on wake time after sleep onset (WASO), total sleep time (TST), sleep efficiency (SE), and total PSQI scores, but not the sleep onset latency (SOL). Conclusions Eight weeks of the zolpidem combined with paroxetine treatment to patients with primary insomnia is more effective than zolpidem treatment only in sleep maintenance and early morning awakenings.