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Two-dimensional (2D) semiconductors have recently attracted considerable attention due to their promising applications in future integrated electronic and optoelectronic devices. Large-scale synthesis of high-quality 2D semiconductors is an increasingly essential requirement for practical applications, such as sensing, imaging, and communications. In this work, homogeneous 2D GaTe films on a centimeter scale are epitaxially grown on fluorphlogopite mica substrates by molecular beam epitaxy (MBE). The epitaxial GaTe thin films showed an atomically 2D layered lattice structure with a T phase, which has not been discovered in the GaTe geometric isomer. Furthermore, semiconducting behavior and high mobility above room temperature were found in T-GaTe epitaxial films, which are essential for application in semiconducting devices. The T-GaTe-based photodetectors demonstrated respectable photodetection performance with a responsivity of 13 mA/W and a fast response speed. By introducing monolayer graphene as the substrate, we successfully realized high-quality GaTe/graphene heterostructures. The performance has been significantly improved, such as the responsivity was enhanced more than 20 times. These results highlight a feasible scheme for exploring the crystal phase of 2D GaTe and realizing the controlled growth of GaTe films on large substrates, which could promote the development of broadband, high-performance, and large-scale photodetection applications.

Hydrophilic interaction liquid chromatography (HILIC) is widely used for glycopeptide enrichment in shot-gun glycoproteomics to enhance the glycopeptide signal and minimize the ionization competition of peptides. In this work, we have developed a novel hydrophilic material (glycoHILIC) based on glycopeptides and peptides to provide hydrophilic properties. GlycoHILIC was synthesized by oxidizing cotton and then reacting the resulting aldehyde with the N-terminus of the glycopeptide or peptide by reductive amination. Due to the large amount of hydrophilic carbohydrates and hydrophilic amino acids contained in glycopeptides, glycoHILIC showed significantly better enrichment of glycopeptides than cotton itself. Our results demonstrate that glycoHILIC has high selectivity, a low detection limit, and good stability. Over 257 unique N-linked glycosylation sites in 1477 intact N-glycopeptides from 146 glycoproteins were identified from 1 μL of human serum using glycoHILIC. Serum analysis of pancreatic cancer patients found that 38 N-glycopeptides among 21 glycoproteins changed significantly, of which 7 N-glycopeptides increased and 31 N-glycopeptides decreased. These results demonstrate that glycoHILIC can be used for glycopeptide enrichment and analysis.

We discuss regression analysis of current status data with the additive hazards model when the failure status may suffer misclassification. Such data occur commonly in many scientific fields involving the diagnosis test with imperfect sensitivity and specificity. In particular, we consider the situation where the sensitivity and specificity are known and propose a nonparametric maximum likelihood approach. For the implementation of the method, a novel EM algorithm is developed, and the asymptotic properties of the resulting estimators are established. Furthermore, the estimated regression parameters are shown to be semiparametrically efficient. We demonstrate the empirical performance of the proposed methodology in a simulation study and show its substantial advantages over the naive method. Also an application to a motivated study on chlamydia is provided.

Interval-censored failure time data arise frequently in periodical follow-up studies including clinical trials and epidemiological surveys. In addition, some covariates may be subject to measurement errors due to the instrumental contamination, biological variation or other reasons. For the analysis of interval-censored data with mis-measured covariates, the existing methods either assume a parametric model or rely on the availability of replicated surrogate measurements for the error-prone covariate, which both have obvious limitations. To overcome these shortcomings, the authors propose a simulation-extrapolation estimation procedure under a general class of transformation models. The resulting estimators are shown to be consistent and asymptotically normal. The numerical results obtained from a simulation study indicate that the proposed method performs reasonably well in practice. In particular, the proposed method can reduce the estimation bias given by the naive method that does not take measurement errors into account. Finally, the proposed method is applied to a real data set on hypobaric decompression sickness.

Arecoline is an alkaloid with important pharmacological effects in the plant areca nut, which has been demonstrated to be an agonist of muscarinic receptors (M receptor). This study explored the influences of dietary arecoline on growth performance, intestinal digestion and absorption abilities, antioxidant capacity, and the apical junction complex (AJC) of adult grass carp (Ctenopharyngodon idella). Adult grass carp (608 to 1512 g) were fed at 6 graded levels of dietary arecoline (0, 0.5, 1.0, 1.5, 2.0, and 2.5 mg/kg diet) for 9 weeks. The results suggested that appropriate dietary supplementation of arecoline (1.0 mg/kg) increased growth parameters and intestinal growth in adult grass carp (P < 0.05), enhanced digestion and absorption capacities (P < 0.05), up-regulated muscarinic receptor 3 (M3) mRNA level (P < 0.05), increased the content of neuropeptide fish substance P (P < 0.05), improved antioxidant capacity by activating the Keap1a/Nrf2 signaling pathway (P < 0.05), reduced intestinal mucosal permeability (P < 0.05), and increased mRNA levels of tight junction (TJ) and adherent junction AJ-related proteins in fish by inhibiting the RhoA/ROCK signaling pathway (RhoA/ROCK/MLCK/NMII) (P < 0.05). In addition, the appropriate arecoline supplementation for adult grass carp was determined to be 1.20, 1.21, 1.07, and 1.19 mg/kg based on percentage weight gain, lipase activity, serum diamine oxidase, and protein carbonyl, respectively. Overall, to the best of our knowledge, we investigated for the first time the effects and possible mechanisms of dietary arecoline on intestinal digestive and absorptive capacities and structural integrity in fish and evaluated the appropriate level of supplementation.

Peptide labeling by isobaric tags is a powerful approach for the relative quantitative analysis of proteomes in multiple groups. There has been a revolution in the innovation of new isobaric reagents; however, great effort is being made to expand simultaneous labeling groups to identify more labeled peptides and reduce reporter ion signal suppression. We redesigned the original chemical structure of the deuterium isobaric amine-reactive tag developed in our laboratory. We optimized the synthetic pathway to create a new set of 16-plex isobaric tags (IBT-16plex). The novel reagent enabled almost complete labeling of peptides within 90 min, with all labeling reporter ions exhibiting comparable MS/MS signals. Compared to a typical 16plex reagent, TMTpro-16plex, the peptides and proteins identified by IBT-16plex in trypsinized HeLa cells were significantly increased by 14.8 and 8.6%, respectively. Moreover, differences in peptide abundance within 10-fold among multiple groups were barely suppressed in IBT-16plex, whereas the dynamic range in TMTpro-16plex-labeled groups was smaller. After quantitative examination of MCF7 cell proteins, IBT-16plex was confirmed as feasible and useful for evaluating protein responses of glucose-starved MCF7 cells to a glucose-rich medium.

Element contamination, including that from heavy metals, is associated with gastrointestinal tumorigenesis, but the effects and mechanisms of crucial element exposure associated with colorectal cancer remain unclear. We profiled 56 elements by ICP-MS and used logistic regression, LASSO, BKMR, and GAM to identify colorectal cancer-relevant elements. A series of biochemical experiments were performed to demonstrate the cytotoxicity and the mechanisms of malignant transformation after metal exposure. Using an elementomics approach, we first found that the metal thallium (Tl) was positively correlated with many toxic metals and was associated with a significantly increased risk of colorectal cancer. Acute exposure to Tl induced cytotoxicity and cell death by accelerating the generation of reactive oxygen species and DNA damage. Chronic exposure to Tl led to the inhibition of cell death and thereby induced the malignant transformation of normal colon cells and xenograft tumor formation in nude mice. Furthermore, we describe the first identification of a significant metal quantitative trait locus for the novel colorectal cancer susceptibility locus rs1511625 near ATP13A3. Mechanistically, Tl increased the level of aberrant N6-methyladenosine (m6A) modification of ATP13A3via the METLL3/METTL14/ALKBH5-ATP13A3axis to promote colorectal tumorigenesis. This study provides a basis for the development of public health strategies for reducing metal exposure among populations at high risk for colorectal cancer.

The field of topological photonics was initiated with the realization of a Chern insulator phase in a gyromagnetic photonic crystal (PhC) with broken time-reversal symmetry (T), hosting chiral edge states that are topologically protected propagating modes. Along a separate line of research, a quadrupole topological insulator was the first higher-order topological phase supporting localized corner states, but has been so far limited to T-invariant systems, as Tis a key ingredient in early models. Here we report the realization of a quadrupole topological insulator phase in a gyromagnetic PhC, as a consequence of topological phase transition from the previously demonstrated Chern insulator phase. The phase transition has been demonstrated with microwave measurements, which characterize the evolution from propagating chiral edge states to localized corner states. We also demonstrate the migration of topological boundary states into the continuum, when the gyromagnetic PhC is magnetically tuned. These results extend the quadrupole topological insulator phase into T-broken systems, and integrate topologically protected propagating and localized modes in a magnetically tunable photonic crystal platform.Realization of a quadrupole topological insulator (QTI) phase in a gyromagnetic photonic crystal broadens the realm of QTI phases to encompass time-reversal symmetry-broken systems and holds the potential to integrate topologically protected unidirectional propagating and localized states in a single photonic platform.

Objective: This study was conducted to explore the causal associations of high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglyceride (TG) with the risk of upper gastrointestinal cancers (esophageal cancer [EC] and gastric cancer [GC]). Methods: A total of 5623 Chinese and 4133 Europeans afforded the individual-level genotyping data, and 203,608 Japanese from Biobank Japan project and 393,926 Europeans from UK Biobank supported summary statistics of cancer genetic associations. Mendelian randomization (MR) analyses, including weighted genetic risk scores (wGRSs), inverse-variance weighted (IVW), weighted median and Egger-regression, were utilized to evaluate the causal effects of three blood lipids on upper gastrointestinal cancers risk. Results: There was no significantly causal relationships between three blood lipids and EC or GC risk among Chinese or Europeans but a potential causal association between TG and GC risk among Japanese (IVW: odds ratio [OR] = 1.11, P= 0.034; Phet= 0.679). In stratified subgroups, higher genetically predicted TG levels were causally associated with an increased risk of GC among Chinese males (wGRS: OR = 1.61, P= 0.021; IVW: OR = 1.57, P= 0.009; Phet= 0.653) and Japanese females (IVW: OR = 1.33, P= 0.024; Phet= 0.378). Conclusion: This trans-ancestry MR study suggested null significant causality between serum HDL, LDL or TG and the risk of upper gastrointestinal cancers among Chinese and Europeans, but provided evidence for a causal role of TG involved in GC etiology in Japanese (especially females), which would support a prevention guide for high-risk groups of GC. Further research with more comprehensive information is needed to explore the underlying mechanism.

Primary colon cancers arising from the left and right sides exhibit distinct clinical and molecular characteristics. Sidedness-associated heterogeneity relies intricately on the oncogenic properties of cancer cells and multicellular interactions in tumor microenvironments. Here, combining transcriptomic profiling of 426,863 single cells from 105 colon cancer patients and validation with spatial transcriptomics and large-scale histological analysis, we capture common transcriptional heterogeneity patterns between left- and right-sided malignant epithelia through delineating two side-specific expression meta-programs. The proliferation stemness meta-program is notably enriched in left-sided malignant epithelia that colocalize with Mph-PLTP cells, activated regulatory T cells (Tregs), and exhausted CD8-LAYN cells, constituting the glucose metabolism reprogramming niche. The immune secretory (IS) meta-program exhibits specific enrichment in right-sided malignant epithelia, especially in smoking patients with right-sided colon cancer. The IShighmalignant epithelia spatially localize in hypoxic regions and facilitate immune evasion through attenuating Mph-SPP1 cell antigen presentation and recruiting innate-like cytotoxicity-reduced CD8-CD161 cells.

Protein glycosylation is one of the most important post-translational modifications, and aberrant glycosylation is associated with the occurrence and development of diseases. Deciphering abnormal glycosylation changes can identify disease-specific signatures to facilitate the discovery of potential disease biomarkers. However, glycosylation analysis is challenging due to the diversity of glycans, heterogeneity of glycosites, and poor electrospray ionization of mass spectrometry. To overcome these obstacles, glycosylation is often elucidated using enriched glycopeptides by removing highly abundant non-glycopeptides. Hydrophilic interaction liquid chromatography (HILIC) is widely used for glycopeptide enrichment due to its excellent selectivity and specificity to hydrophilic glycans and compatibility with mass spectrometry. However, the development of HILIC has lagged far behind hydrophobic interaction chromatography, so efforts to further improve the performance of HILIC are beneficial for glycosylation analysis. This review discusses recent developments in HILIC materials and their advanced applications. Based on the physiochemical properties of glycopeptides, the use of amino acids or peptides as stationary phases showed improved enrichment and separation of glycopeptides. We can envision that the use of glycopeptides as stationary phases would definitely further improve the selectivity and specificity of HILIC for glycosylation analysis.

Oxygen evolution reaction (OER) as the foremost stumbling block to generate cost-effective clean fuels has received extensive attention in recent years. But, it still maintains the challenge to manipulate the geometric and electronic structure during single reaction process under the same conditions. Herein, we report a simple self-template strategy to generate honeycomb-like Ni2P/N,P–C hybrids with preferred electronic architecture. Experiments coupled with theoretical results revealed that the synthesized catalyst has two characteristics: firstly, the unique honeycomb-like morphology not only enables the fully utilization of catalytic active sites but also optimizes the mass/electron transportation pathway, which favor the diffusion of electrolyte to accessible active sites. Secondly, N,P–C substrate, on the one hand, largely contributes the electronic distribution near Fermi level (EF) thus boosting its electrical conductivity. On the other hand, the support effect result in the upshift of d-band center and electropositivity of Ni sites, which attenuates the energy barrier for the adsorption of OH−and the formation of ∗OOH. In consequence, the optimized Ni2P/N,P–C catalysts feature high electrocatalytic activity towards OER (a low overpotential of 252 mV to achieve 10 mA cm−2) and 10 h long-term stability, the outstanding performance is comparable to most of transition metal catalysts. This work gives a innovative tactics for contriving original OER electrocatalysts, inspirng deeper understanding of fabricating catalysts by combining theoretical simulation and experiment design.

Mid-infrared (MIR) photodetection is of significance in civil and military applications because it shows superiority in absorbing the vibration of various molecules and covering atmospheric transmission windows. Recently, the PtTe2, a typical type-II Dirac semimetal, has come under the spotlight due to its unique photodetection sensibility in the MIR region and robust stability in the atmosphere. Here, the high-quality and large-scale 1T-PtTe2thin films with air stability were grown by molecular beam epitaxy. Broadband photoresponse of the photodetectors of PtTe2from 420 nm to 10.7 μm shows high responsivity and detectivity of 0.2 mA W–1and 2.6 × 107Jones at 10.7 μm and 1.6 mA W–1and 2.2 × 108Jones at 4.7 μm under the atmosphere, respectively. Moreover, the photodetectors exhibit high sensitivity in visible and near-infrared regions (8.2 mA W–1at 650 nm and 15.6 mA W–1at 960 nm). The power- and polarization-dependent photoresponse measurements reveal the linear relationship of power photoresponse and obvious anisotropic photoresponse (the ratio of anisotropy ellipse is 8.3 at 10.7 μm), respectively. These results suggest that the PtTe2could be expected to be an advanced photodetection material for polarization angle-sensitive detection, infrared imaging, and photodetection from the visible to MIR range.

Lithium-rich manganese-based layered oxide cathodes (LLOs) with oxygen redox reactions are considered to be potential candidates for the next generation of high-energy-density Li-ion batteries. However, the oxygen redox process that enables ultrahigh specific capacity usually leads to irreversible O2release and cation migration, which induce structure degradation and severe capacity/voltage losses and thus limit the commercial application of LLOs. Herein, we successfully synthesized chlorine (Cl)-doped Co-free LLOs (Li1.2Mn0.53Ni0.27O1.976Cl0.024) and analyzed the effect of anion doping on oxygen redox and structure stability of LLOs. Cl doping has been proven to decrease the irreversible lattice oxygen loss to enhance the redox reversibility of oxygen and inhibit the transition-metal migration during cycles, which substantially enhances the capacity and voltage retention and improves the rate capability during cycling. This work provides new insights for the development of high-performance TM oxide cathode materials with reversible oxygen redox.

The enhancement of electron–phonon interaction provides a reasonable explanation for gate-tunable phonon properties in some semiconductors where multiple inequivalent valleys are simultaneously occupied upon charge doping, especially in few-layer transition metal dichalcogenides (TMDs). In this work, we report var der Waals epitaxy of 2H-MoSe2by molecular beam epitaxy (MBE) and gate-tunable phonon properties in monolayer and bilayer MoSe2. In monolayer MoSe2, we find that out-of-plane phonon mode A1gexhibits a strong softening and shifting toward lower wavenumbers at a high electron doping level, while in-plane phonon mode E2g1remains unchanged. The softening and shifting of the out-of-plane phonon mode could be attributed to the increase of electron–phonon interaction and the simultaneous occupation of electrons in multiple inequivalent valleys. In bilayer MoSe2, no corresponding changes of phonon modes are detected at the same doping level, which could originate from the occupation of electrons only in single valleys upon high electron doping. This study demonstrates electrostatically enhanced electron–phonon interaction in monolayer MoSe2and clarifies the relevance between occupation of multiple valleys and phonon properties by comparing Raman spectra of monolayer and bilayer MoSe2at different doping levels.

Rare germline mutations in several genes, primarily DNA repair genes, have been proposed to predict worse prognosis of prostate cancer (PCa).

Azobenzene (AZO) has attached tremendous attention in the field of photo-isomerization energy storage due to its advantages of absorbing light in ultraviolet-visible range and reversible isomerization. However, the issues of low energy density and short half-lifetime restrict the further development of AZO. Therefore, a method, by preparing hybrid photo-isomerization energy storage materials using nanoscale templates, was proposed to handle the above two issues. In this paper, a summary of hybrid photo-isomerization energy storage materials with AZO and nanoscale templates is conducted from the aspects of templates, preparation methods, derivatives and applications. The performances of template candidates, i.e. carbon nanotubes (CNTs) and graphene (GO) are reviewed and compared based on the analysis of grafting density, energy density, and half-lifetime of hybrid materials. Then, two major preparation methods of AZO hybrid materials including non-covalent and covalent functionalizations are discussed. Furthermore, the studies on AZO derivatives functionalized on nanoscale templates are summarized to further point to the direction of derivatization towards high performance AZO-functionalized materials. Finally, due to the superiority of AZO hybrid solid-state films in large-scale utilization, their current applications are reviewed to find out some promising applications.

BackgroundPathogenic variants in mismatch repair (MMR) genes (MLH1, MSH2, MSH6and PMS2) increase risk for Lynch syndrome and related cancers. We quantified tumour characteristics to assess variant pathogenicity for germline MMR genes.MethodsAmong 4740 patients with cancer with microsatellite instability (MSI) and immunohistochemical (IHC) results, we tested MMR pathogenic variant association with MSI/IHC status, and estimated likelihood ratios which we used to compute a tumour characteristic likelihood ratio (TCLR) for each variant. Predictive performance of TCLRin combination with in silicopredictors, and a multifactorial variant prediction (MVP) model that included allele frequency, co-occurrence, co-segregation, and clinical and family history information was assessed.ResultsCompared with non-carriers, carriers of germline pathogenic/likely pathogenic (P/LP) variants were more likely to have abnormal MSI/IHC status (p<0.0001). Among 150 classified missense variants, 73.3% were accurately predicted with TCLRalone. Models leveraging in silicoscores as prior probabilities accurately classified >76.7% variants. Adding TCLRas quantitative evidence in an MVP model (MVP +TCLRPred) increased the proportion of accurately classified variants from 88.0% (MVP alone) to 98.0% and generated optimal performance statistics among all models tested. Importantly, MVP +TCLRPredresulted in the high yield of predicted classifications for missense variants of unknown significance (VUS); among 193 VUS, 62.7% were predicted as P/PL or benign/likely benign (B/LB) when assessed according to American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines.ConclusionOur study demonstrates that when used separately or in conjunction with other evidence, tumour characteristics provide evidence for germline MMR missense variant assessment, which may have important implications for genetic testing and clinical management.

There has been a huge discrepancy between the vacuum energy density calculated based on the existing quantum theories and the observational values. The calculated vacuum energy density is about 120 orders of magnitude greater than its observational values, which is one of the worst theoretical predictions in the history of modern physics. As a promising quantum gravity theory, the newly developed fractal quantum gravity (FQG) theory has introduced the smallest constant of the product of space, time and energy of Space-Time Quantum of Action (STQA). The product of space, time and energy of every particle is integer times of this smallest constant — STQA. Based on the FQG equation, we have calculated the vacuum energy density which is a perfect match with its observational values. This recent development has shed much insight into the intrinsic nature of vacuum and it will continue to provide guidance of future research in the area of dark energy.

Objective To describe clinicoradiological features and outcomes of reversible splenial lesion syndrome (RESLES) in children.Methods Data from 23 children (25 RESLES episodes; two patients had recurring episodes) was retrospectively reviewed at the Department of Pediatric Neurology, Shandong Provincial Hospital Affiliated with Shandong University, China. Primary disease, central nervous system manifestations, treatments, outcomes, and laboratory examination, electroencephalogram, and magnetic resonance imaging (MRI) results were assessed.Results Fourteen boys and nine girls (23 patients; 8 months to 11 years old) with 25 RESLES episodes (20 type-1, 5 type-2) were enrolled. Epileptic seizure and infection were the most common pathogenesis. Prominent clinical manifestations were disturbance of consciousness and visual disturbance. Cranial MRI of 20 RESLES type-1 episodes showed oval lesions in the splenium of corpus callosum (SCC), and five RESLES type-2 episodes showed lesions in the entire corpus callosum that were associated with the symmetric cerebral white matter. Lesions were hyperintense on diffusion-weighed images (DWI) and disappeared when later reviewed (range, 4–30 days).Conclusions RESLES etiology in children is complex, and its clinical manifestations are nonspecific. Diagnosis mainly depends on cranial MRI, especially DWI, showing highly intense lesions on SCC. RESLES has a good prognosis and excessive treatment should be avoided.

Electrocatalytic synthesis of hydrogen peroxide (H2O2) in acidic media is an efficient and eco-friendly approach to produce inherently stable H2O2, but limited by the lack of selective and stable catalysts under industrial-relevant current densities. Herein, we report a diatomic cobalt catalyst for two-electron oxygen reduction to efficiently produce H2O2at 50–400 mA cm–2in acid. Electrode kinetics study shows a >95% selectivity for two-electron oxygen reduction on the diatomic cobalt sites. In a flow cell device, a record-high production rate of 11.72 mol gcat–1h–1and exceptional long-term stability (100 h) are realized under high current densities. In situspectroscopic studies and theoretical calculations reveal that introducing a second metal into the coordination sphere of the cobalt site can optimize the binding strength of key H2O2intermediates due to the downshifted d-band center of cobalt. We also demonstrate the feasibility of processing municipal plastic wastes through decentralized H2O2production.

Charge density wave phase comprises a periodic modulation of the electronic charge density with a periodic distortion of the atomic lattice, and transition-metal dichalcogenides are very important subjects for the study of this distortion. In this work, large-area 1T′-vanadium telluride (VTe2) films grown by molecular beam epitaxy show the charge density wave order down to the few-layer limit. The film thickness was found to be strongly correlated with the out-of-plane vibration mode shifting from Raman scattering, and increasing film thickness leads to an insulating-metallic transition. We demonstrate a charge density wave phase transition at 175 K for 2 (ML) films and multiple phase transitions in films more than 5 ML. It was also found that the transition was accompanied with a strong out-of-plane distortion. These findings open up a new window for the search and control of collective phases of two-dimensional VTe2films.

Current-induced magnetization switching was investigated in Au/Fe4N bilayer films grown by a plasma-assisted molecular beam epitaxy (PA-MBE) system. Depending on lattice distortion and interfacial coupling induced by substrates, the Fe4N layer could be divided into two sublayers having different magnetic anisotropies. The bottom sublayer shows perpendicular magnetic anisotropy (PMA), while the top one has in-plane magnetic anisotropy (IMA). Coupling between the two sublayers provides an extra in-plane effective field and enables a field-free magnetization switching in the bilayer films. By summarizing a series of Hall measurements, a switching phase diagram was obtained. Temperature-dependent switching behaviors demonstrate that the threshold current density for the field-free magnetization switching, which is much smaller than that of pervious reports, increases with decreasing temperature and shows similar temperature dependences to those of coercivity.

Charge density wave (CDW) as a novel effect in two-dimensional transition metal dichalcogenides (TMDs) has obtained a rapid rise of interest for its physical nature and potential applications in oscillators and memory devices. Here, we report var der Waals epitaxial growth of centimeter-scale 1T-VTe2thin films on mica by molecular beam epitaxy. The VTe2thin films showed sudden resistance change at temperatures of 240 and 135 K, corresponding to two CDW phase transitions driven by temperature. Moreover, the phase transitions can be driven by an electric field due to local Joule heating, and the corresponding resistance states are nonvolatile and controllable, which could be applied to the memory device where the logic states can be switched by an electric field. The multistage CDW phase transitions in the VTe2thin films could be contributed to electron–phonon coupling in the two-dimensional VTe2, which is supported by twice pronounced Raman blue shifts of the vibration modes associated with in-plane phonons at CDW phase transition temperature. The results open up a new platform for understanding the microscopic physical essence and electrical control of CDW phases of TMDs, expanding the functionalities of these materials for memory applications.

IMPORTANCE: Since the discovery of BRCA1 and BRCA2, multiple high- and moderate-penetrance genes have been reported as risk factors for hereditary breast cancer, ovarian cancer, or both; however, it is unclear whether these findings represent the complete genetic landscape of these cancers. Systematic investigation of the genetic contributions to breast and ovarian cancers is needed to confirm these findings and explore potentially new associations. OBJECTIVE: To confirm reported and identify additional predisposition genes for breast or ovarian cancer. DESIGN, SETTING, AND PARTICIPANTS: In this sample of 11 416 patients with clinical features of breast cancer, ovarian cancer, or both who were referred for genetic testing from 1200 hospitals and clinics across the United States and of 3988 controls who were referred for genetic testing for noncancer conditions between 2014 and 2015, whole-exome sequencing was conducted and gene-phenotype associations were examined. Case-control analyses using the Genome Aggregation Database as a set of reference controls were also conducted. MAIN OUTCOMES AND MEASURES: Breast cancer risk associated with pathogenic variants among 625 cancer predisposition genes; association of identified predisposition breast or ovarian cancer genes with the breast cancer subtypes invasive ductal, invasive lobular, hormone receptor–positive, hormone receptor–negative, and male, and with early-onset disease. RESULTS: Of 9639 patients with breast cancer, 3960 (41.1%) were early-onset cases (≤45 years at diagnosis) and 123 (1.3%) were male, with men having an older age at diagnosis than women (mean [SD] age, 61.8 [12.8] vs 48.6 [11.4] years). Of 2051 women with ovarian cancer, 445 (21.7%) received a diagnosis at 45 years or younger. Enrichment of pathogenic variants were identified in 4 non-BRCA genes associated with breast cancer risk: ATM (odds ratio [OR], 2.97; 95% CI, 1.67-5.68), CHEK2 (OR, 2.19; 95% CI, 1.40-3.56), PALB2 (OR, 5.53; 95% CI, 2.24-17.65), and MSH6 (OR, 2.59; 95% CI, 1.35-5.44). Increased risk for ovarian cancer was associated with 4 genes: MSH6 (OR, 4.16; 95% CI, 1.95-9.47), RAD51C (OR, not estimable; false-discovery rate–corrected P = .004), TP53 (OR, 18.50; 95% CI, 2.56-808.10), and ATM (OR, 2.85; 95% CI, 1.30-6.32). Neither the MRN complex genes nor CDKN2A was associated with increased breast or ovarian cancer risk. The findings also do not support previously reported breast cancer associations with the ovarian cancer susceptibility genes BRIP1, RAD51C, and RAD51D, or mismatch repair genes MSH2 and PMS2. CONCLUSIONS AND RELEVANCE: The results of this large-scale exome sequencing of patients and controls shed light on both well-established and controversial non-BRCA predisposition gene associations with breast or ovarian cancer reported to date and may implicate additional breast or ovarian cancer susceptibility gene candidates involved in DNA repair and genomic maintenance.

BackgroundThe clinical phenotype of CDH1pathogenic variant carriers has mostly been studied in families that fulfil criteria of hereditary diffuse gastric cancer (HDGC). We aimed at determining cancer phenotype and cancer risk estimation among families with CDH1pathogenic variants not selected by HDGC clinical criteria.MethodsPatients were all consecutively identified CDH1pathogenic variant carriers from a clinical laboratory tested with multigene panel testing and from an academic cancer genetics programme. Clinical and demographic features, cancer phenotypes and genotype–phenotype correlations were determined among CDH1families. Age-specific cumulative cancer risks (penetrance) were calculated based on 38 families with available pedigrees.ResultsWithin the 113 CDH1pathogenic variant probands and 476 relatives, 113 had gastric cancer, 177 breast cancer and 196 other cancers. Mean age at diagnosis was 47 for gastric and 54 for breast cancer. Forty-six per cent fulfilled criteria of HDGC. While 36% of families had both gastric and breast cancers, 36% had breast but no gastric cancers and 16% had gastric but not breast cancers. Cumulative risk of cancer by age 80 was 37.2% for gastric and 42.9% for breast cancer.ConclusionIn unselected CDH1pathogenic variant carrier families, gastric cancer risks were lower and age at diagnosis higher than previously reported in families pre-selected for HDGC criteria. A substantial proportion of families did not present with any gastric cancers and their cancers were limited to breast. Thus, clinical criteria for CDH1testing should be widened, including breast cancer families only, and a consideration for delayed prophylactic gastrectomy/surveillance should be evaluated.

Currently, the commercial reagents for isobaric peptides labeling (TMT and iTRAQ) have some drawbacks, such as high cost in experiments, especially in quantitation for the modified peptides, and inconvenient handling for variable sizes of samples. Herein, we developed a set of 10-plex isobaric tags (IBT) with high stability and low cost. The labeled peptides were sensitively detected on Orbitrap Q Exactive MS with an MS2 resolution of 35 000 at 30% NCE, while the peptides were efficiently labeled over 97% by IBT at a ratio of 10:1 of reagent/peptide (w/w) in 200 mM TEAB buffer for 2 h. The IBT labeling was demonstrated with a wide dynamic range of 50-fold without obvious matrix effects on quantification. Importantly, there was little quantification bias found among the individual IBT tags, indicating that the peptides labeled by different tags were quantitatively comparable. The IBT 10-plex reagents were applied for dynamically monitoring the quantitative responses of phosphoproteome stimulated by EGF treatment in HeLa cells. In total, 5 361 unique phosphopeptides were identified, which reached a similar conclusion as others reported. The IBT reagents were therefore experimentally proven as a new type of reagents for isobaric peptides labeling and useful in a large quantity peptides of quantitative proteomics.

Diagnostic exome sequencing (DES) is now a commonly ordered test for individuals with undiagnosed genetic disorders. In addition to providing a diagnosis for characterized diseases, exome sequencing has the capacity to uncover novel candidate genes for disease.

Purpose:Diagnostic exome sequencing (DES) is now a commonly ordered test for individuals with undiagnosed genetic disorders. In addition to providing a diagnosis for characterized diseases, exome sequencing has the capacity to uncover novel candidate genes for disease.Methods:Family-based DES included analysis of both characterized and novel genetic etiologies. To evaluate candidate genes for disease in the clinical setting, we developed a systematic, rule-based classification schema.Results:Testing identified a candidate gene among 7.7% (72/934) of patients referred for DES; 37 (4.0%) and 35 (3.7%) of the genes received evidence scores of “candidate” and “suspected candidate,” respectively. A total of 71 independent candidate genes were reported among the 72 patients, and 38% (27/71) were subsequently corroborated in the peer-reviewed literature. This rate of corroboration increased to 51.9% (27/52) among patients whose gene was reported at least 12 months previously.Conclusions:Herein, we provide transparent, comprehensive, and standardized scoring criteria for the clinical reporting of candidate genes. These results demonstrate that DES is an integral tool for genetic diagnosis, especially for elucidating the molecular basis for both characterized and novel candidate genetic etiologies. Gene discoveries also advance the understanding of normal human biology and more common diseases.Genet Med 19 2, 224–235.

Incidence of early-onset colorectal cancer (EOCRC), defined by a diagnosed age under 50 years, is increasing, but its heterogeneous etiologies that differ from general CRC remain undetermined. We initially characterize the genome, epigenome, transcriptome, and proteome of tumors from 79 patients in a Chinese CRC cohort. Data for an additional 126 EOCRC subjects are obtained from the International Cancer Genome Consortium Chinese cohort and The Cancer Genome Atlas European cohort. We observe that early-onset tumors have a high tumor mutation burden; increased DNA repair features by mutational signature 3 and multi-layer pathway enrichments; strong perturbations at effects of DNA methylation and somatic copy-number alteration on gene expression; and upregulated immune infiltration as hottumors underlying immunophenotypes. Notably, LMTK3exhibits ancestral mutation disparity, potentially being a functional modulator and biomarker that drives molecular alterations in EOCRC development and immunotherapies. This integrative omics study provides valuable knowledge for precision oncology of CRC.

Isobaric labeling has emerged as an indispensable quantitative proteomic approach for its unprecedented multiplexing capacity in a single analysis. Currently, different hyperplexing approaches have been developed to meet the demand for the increasing sample size in large-scale cohort analysis. In this report, we present a tribrid hyperplexing approach by the combinatorial use of three types of isobaric reagents, a novel isobaric tag 16-plex (IBT16) reagent and the widely used tandem mass tag (TMT; TMT11) and TMTpro (TMT18) reagents. After the determination of labeling efficiency and the optimization of testing conditions, we systematically evaluated the identification and quantification performance of the three labeling reagents in both independent and combinatorial manners using the mixtures of E. coliand HeLa peptides with different ratios. Our results reveal that the three reagents are quite similar in all testing aspects despite some differences, and the combination use of the three reagents could expand the multiplexing capacity to up to 45-plex. Furthermore, we conclude the advantages of IBT16 in the combination use and the preferred combinations for different practical applications. Data are available via ProteomeXchange with identifier PXD037498.

Based on the smallest physical constant of the product of space interval, time interval, and energy, the fractal quantum gravity (FQG) theory has demonstrated that every particle or physical system consists of these smallest units in fractal structures. The general relativity is an approximation of the FQG equation when the quantum effect is negligible, while the quantum theory is an approximation of the FQG equation when the interaction between space, time, and energy is very weak or negligible. The stationary-action principle can be derived from the FQG equation. The mass range of possibly existing elementary particles and an accelerating expansion evolution model of the universe can be obtained through the FQG equation. This FQG equation satisfied almost all the requirements of a quantum gravity theory and there is no free constant needed in the FQG theory. It looks promising that the FQG theory may offer a novel way to calculate all the free constants in the Standard Model of particle physics and general relativity.