•High-entropy boride-carbide two-phase ultrahigh temperature ceramics are made.•This work further extends the emerging field of high-entropy ceramics.•A novel reactive spark plasma sintering route ...produces > ∼99 % dense specimens.•A thermodynamic relation governing the equilibrium phase compositions is discovered.•The hardness is higher than the weighted average of the two high-entropy phases.
A series of dual-phase high-entropy ultra-high temperature ceramics (DPHE-UHTCs) are fabricated starting from N binary borides and (5-N) binary carbides powders. > ∼99 % relative densities have been achieved with virtually no native oxides. These DPHE-UHTCs consist of a hexagonal high-entropy boride (HEB) phase and a cubic high-entropy carbide (HEC) phase. A thermodynamic relation that governs the compositions of the HEB and HEC phases in equilibrium is discovered and a thermodynamic model is proposed. These DPHE-UHTCs exhibit tunable grain size, Vickers microhardness, Young’s and shear moduli, and thermal conductivity. The DPHE-UHTCs have higher hardness than the weighted linear average of the two single-phase HEB and HEC, which are already harder than the rule-of-mixture averages of individual binary borides and carbides. This study extends the state of the art by introducing dual-phase high-entropy ceramics (DPHECs), which provide a new platform to tailor various properties via changing the phase fraction and microstructure.
Control over the number of mtDNA molecules per cell appears to be tightly regulated, but the mechanisms involved are largely unknown. Reversible alterations in the amount of mtDNA occur in response ...to stress suggesting that control over the amount of mtDNA is involved in stress-related diseases including major depressive disorder (MDD). Using low-coverage sequence data from 10,442 Chinese women to compute the normalized numbers of reads mapping to the mitochondrial genome as a proxy for the amount of mtDNA, we identified two loci that contribute to mtDNA levels: one within the TFAM gene on chromosome 10 (rs11006126, p value = 8.73 × 10−28, variance explained = 1.90%) and one over the CDK6 gene on chromosome 7 (rs445, p value = 6.03 × 10−16, variance explained = 0.50%). Both loci replicated in an independent cohort. CDK6 is thus a new molecule involved in the control of mtDNA. We identify increased rates of heteroplasmy in women with MDD, and show from an experimental paradigm using mice that the increase is likely due to stress. Furthermore, at least one heteroplasmic variant is significantly associated with changes in the amount of mtDNA (position 513, p value = 3.27 × 10−9, variance explained = 0.48%) suggesting site-specific heteroplasmy as a possible link between stress and increase in amount of mtDNA. These findings indicate the involvement of mitochondrial genome copy number and sequence in an organism’s response to stress.
•Loci near TFAM and CDK6 contribute to variation in the amount of mtDNA•Mutations accumulate in the mtDNA of cases of major depression•Animal experiments show that heteroplasmy can be induced by chronic stress•Amount of mtDNA is associated with site-specific heteroplasmy
Having previously shown that cases of major depressive disorder have increased mtDNA, that exposure to stress is likely responsible, and that the changes in amount of mtDNA are reversible, Cai et al. investigate in this paper the genetic control and consequences of this change and how this relates to major depressive disorder.
The change in planetary albedo due to aerosol–cloud interactions during the industrial era is the leading source of uncertainty in inferring Earth’s climate sensitivity to increased greenhouse gases ...from the historical record. The variable that controls aerosol–cloud interactions in warm clouds is droplet number concentration. Global climate models demonstrate that the present-day hemispheric contrast in cloud droplet number concentration between the pristine Southern Hemisphere and the polluted Northern Hemisphere oceans can be used as a proxy for anthropogenically driven change in cloud droplet number concentration. Remotely sensed estimates constrain this change in droplet number concentration to be between 8 cm−3 and 24 cm−3. By extension, the radiative forcing since 1850 from aerosol–cloud interactions is constrained to be −1.2 W·m−2 to −0.6 W·m−2. The robustness of this constraint depends upon the assumption that pristine Southern Ocean droplet number concentration is a suitable proxy for preindustrial concentrations. Droplet number concentrations calculated from satellite data over the Southern Ocean are high in austral summer. Near Antarctica, they reach values typical of Northern Hemisphere polluted outflows. These concentrations are found to agree with several in situ datasets. In contrast, climate models show systematic underpredictions of cloud droplet number concentration across the Southern Ocean. Near Antarctica, where precipitation sinks of aerosol are small, the underestimation by climate models is particularly large. This motivates the need for detailed process studies of aerosol production and aerosol–cloud interactions in pristine environments. The hemispheric difference in satellite estimated cloud droplet number concentration implies preindustrial aerosol concentrations were higher than estimated by most models.
While it is now recognized that psychotic experiences are associated with an increased risk of later mental disorders, we lack a detailed understanding of the reciprocal time-lagged relationships ...between first onsets of psychotic experiences and mental disorders. Using data from World Health Organization World Mental Health (WMH) Surveys, the authors assessed the bidirectional temporal associations between psychotic experiences and mental disorders.
The WMH Surveys assessed lifetime prevalence and age at onset of psychotic experiences and 21 common DSM-IV mental disorders among 31,261 adult respondents from 18 countries. Discrete-time survival models were used to examine bivariate and multivariate associations between psychotic experiences and mental disorders.
Temporally primary psychotic experiences were significantly associated with subsequent first onset of eight of the 21 mental disorders (major depressive disorder, bipolar disorder, generalized anxiety disorder, social phobia, posttraumatic stress disorder, adult separation anxiety disorder, bulimia nervosa, and alcohol abuse), with odds ratios ranging from 1.3 (95% CI=1.2-1.5) for major depressive disorder to 2.0 (95% CI=1.5-2.6) for bipolar disorder. In contrast, 18 of 21 primary mental disorders were significantly associated with subsequent first onset of psychotic experiences, with odds ratios ranging from 1.5 (95% CI=1.0-2.1) for childhood separation anxiety disorder to 2.8 (95% CI=1.0-7.8) for anorexia nervosa.
While temporally primary psychotic experiences are associated with an elevated risk of several subsequent mental disorders, these data show that most mental disorders are associated with an elevated risk of subsequent psychotic experiences. Further investigation of the underlying factors accounting for these time-order relationships may shed light on the etiology of psychotic experiences.
Background
Small cohort studies have suggested oral tongue squamous cell carcinoma (OTSCC) could be associated with worse prognosis in individuals younger than 40.
Methods
We compared the survival of ...all OTSCC cases in the National Cancer Database under 40 years old with those older than 40, excluding patients over 70. Cox regression and propensity score matched (PSM) survival analyses were performed.
Results
A total of 22 930 OTSCC patients were identified. The under 40 group consisted of 2566 (9.9%) cases; 20664 were 40 to 70 (90.1%). Most were male (13 713, 59.8%), stage I‐II (12 754, 72.4%), and treated by surgery alone (13 973, 63.2%). Survival in patients under 40 was higher (79.6% vs 69.5%, P < .001). In PSM analysis (n = 2928) controlling for all 10 significant factors in multivariate regression, patients under 40 had a 9% higher 5‐year survival (77.1% vs 68.2%, P < .001).
Conclusion
Contrary to the prior reports, younger patients with OTSCC did not have worse survival in the National Cancer Database.
Summary In this Review, we summarise recent published work on the use of intraoperative radiotherapy to treat common tumour sites in the primary or recurrent setting. Techniques, radiobiology, and ...the physics of intraoperative radiotherapy are also explored. Disease sites discussed in this Review include head and neck cancer, breast cancer, sarcoma, gastrointestinal cancer, genitourinary cancer, gynaecological cancer, thoracic cancer, and palliative applications.
Whereas ferromagnets have been known and used for millennia, antiferromagnets were only discovered in the 1930s.sup.1. At large scale, because of the absence of global magnetization, antiferromagnets ...may seem to behave like any non-magnetic material. At the microscopic level, however, the opposite alignment of spins forms a rich internal structure. In topological antiferromagnets, this internal structure leads to the possibility that the property known as the Berry phase can acquire distinct spatial textures.sup.2,3. Here we study this possibility in an antiferromagnetic axion insulator--even-layered, two-dimensional MnBi.sub.2Te.sub.4--in which spatial degrees of freedom correspond to different layers. We observe a type of Hall effect--the layer Hall effect--in which electrons from the top and bottom layers spontaneously deflect in opposite directions. Specifically, under zero electric field, even-layered MnBi.sub.2Te.sub.4 shows no anomalous Hall effect. However, applying an electric field leads to the emergence of a large, layer-polarized anomalous Hall effect of about 0.5e.sup.2/h (where e is the electron charge and h is Planck's constant). This layer Hall effect uncovers an unusual layer-locked Berry curvature, which serves to characterize the axion insulator state. Moreover, we find that the layer-locked Berry curvature can be manipulated by the axion field formed from the dot product of the electric and magnetic field vectors. Our results offer new pathways to detect and manipulate the internal spatial structure of fully compensated topological antiferromagnets.sup.4-9. The layer-locked Berry curvature represents a first step towards spatial engineering of the Berry phase through effects such as layer-specific moiré potential.
Osimertinib mesylate is used globally to treat EGFR-mutant non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitor resistance mediated by the EGFR T790M mutation. Acquired resistance to ...osimertinib is a growing clinical challenge that is poorly understood.
To understand the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior.
Patients with advanced NSCLC who received osimertinib for T790M-positive acquired resistance to prior EGFR tyrosine kinase inhibitor were identified from a multi-institutional cohort (n = 143) and a confirmatory trial cohort (NCT01802632) (n = 110). Next-generation sequencing of tumor biopsies after osimertinib resistance was performed. Genotyping of plasma cell-free DNA was studied as an orthogonal approach, including serial plasma samples when available. The study and analysis were finalized on November 9, 2017.
Mechanisms of resistance and their association with time to treatment discontinuation on osimertinib.
Of the 143 patients evaluated, 41 (28 68% women) had tumor next-generation sequencing after acquired resistance to osimertinib. Among 13 patients (32%) with maintained T790M at the time of resistance, EGFR C797S was seen in 9 patients (22%). Among 28 individuals (68%) with loss of T790M, a range of competing resistance mechanisms was detected, including novel mechanisms such as acquired KRAS mutations and targetable gene fusions. Time to treatment discontinuation was shorter in patients with T790M loss (6.1 vs 15.2 months), suggesting emergence of pre-existing resistant clones; this finding was confirmed in a validation cohort of 110 patients with plasma cell-free DNA genotyping performed after osimertinib resistance. In studies of serial plasma levels of mutant EGFR, loss of T790M at resistance was associated with a smaller decrease in levels of the EGFR driver mutation after 1 to 3 weeks of therapy (100% vs 83% decrease; P = .01).
Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms. These data provide clinical evidence of the heterogeneity of resistance in advanced NSCLC and a need for clinical trial strategies that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance.
In diabetes, the death of insulin-producing β-cells by apoptosis leads to insulin deficiency. The lower prevalence of diabetes in females suggests that female sex steroids protect from β-cell injury. ...Consistent with this hypothesis, 17β-estradiol (estradiol) manifests antidiabetic actions in humans and rodents. In addition, estradiol has antiapoptotic actions in cells that are mediated by the estrogen receptor-a (ERα), raising the prospect that estradiol antidiabetic function may be due, in part, to a protection of β-cell apoptosis via ERα. To address this question, we have used mice that were rendered estradiol-deficient or estradiol-resistant by targeted disruption of aromatase (ArKO) or ERα (αERKO) respectively. We show here that in both genders, $ArKO^{-/-}$ mice are vulnerable to P3-cell apoptosis and prone to insulin-deficient diabetes after exposure to acute oxidative stress with streptozotocin. In these mice, estradiol treatment rescues streptozotocin-induced β-cell apoptosis, helps sustain insulin production, and prevents diabetes. In vitro, in mouse pancreatic islets and β-cells exposed to oxidative stress, estradiol prevents apoptosis and protects insulin secretion. Estradiol protection is partially lost in β-cells and islets treated with an ERa antagonist and in αERKO islets. Accordingly, αERKO mice are no longer protected by estradiol and display a gender nonspecific susceptibility to oxidative injury, precipitating β-cell apoptosis and insulin-deficient diabetes. Finally, the predisposition to insulin deficiency can be mimicked in WT mice by pharmacological inhibition of ERα by using the antagonist tamoxifen. This study demonstrates that estradiol, acting, at least in part, through ERα, protects β-cells from oxidative injury and prevents diabetes in mice of both genders.
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