Measurements of All-Particle Energy Spectrum and Mean Logarithmic Mass of Cosmic Rays from 0.3 to 30 PeV with LHAASO-KM2A.

We present the measurements of all-particle energy spectrum and mean logarithmic mass of cosmic rays in the energy range of 0.3-30 PeV using data collected from LHAASO-KM2A between September 2021 and December 2022, which is based on a nearly composition-independent energy reconstruction method, achieving unprecedented accuracy. Our analysis reveals the position of the knee at 3.67±0.05±0.15 PeV. Below the knee, the spectral index is found to be -2.7413±0.0004±0.0050, while above the knee, it is -3.128±0.005±0.027, with the sharpness of the transition measured with a statistical error of 2%. The mean logarithmic mass of cosmic rays is almost heavier than helium in the whole measured energy range. It decreases from 1.7 at 0.3 PeV to 1.3 at 3 PeV, representing a 24% decline following a power law with an index of -0.1200±0.0003±0.0341. This is equivalent to an increase in abundance of light components. Above the knee, the mean logarithmic mass exhibits a power law trend towards heavier components, which is reversal to the behavior observed in the all-particle energy spectrum. Additionally, the knee position and the change in power-law index are approximately the same. These findings suggest that the knee observed in the all-particle spectrum corresponds to the knee of the light component, rather than the medium-heavy components.

Measurement of Ultra-High-Energy Diffuse Gamma-Ray Emission of the Galactic Plane from 10 TeV to 1 PeV with LHAASO-KM2A.

The diffuse Galactic γ-ray emission, mainly produced via interactions between cosmic rays and the interstellar medium and/or radiation field, is a very important probe of the distribution, propagation, and interaction of cosmic rays in the Milky Way. In this Letter, we report the measurements of diffuse γ rays from the Galactic plane between 10 TeV and 1 PeV energies, with the square kilometer array of the Large High Altitude Air Shower Observatory (LHAASO). Diffuse emissions from the inner (15°10 TeV). The energy spectrum in the inner Galaxy regions can be described by a power-law function with an index of -2.99±0.04, which is different from the curved spectrum as expected from hadronic interactions between locally measured cosmic rays and the line-of-sight integrated gas content. Furthermore, the measured flux is higher by a factor of ∼3 than the prediction. A similar spectrum with an index of -2.99±0.07 is found in the outer Galaxy region, and the absolute flux for 10≲E≲60 TeV is again higher than the prediction for hadronic cosmic ray interactions. The latitude distributions of the diffuse emission are consistent with the gas distribution, while the longitude distributions show clear deviation from the gas distribution. The LHAASO measurements imply that either additional emission sources exist or cosmic ray intensities have spatial variations.

A tera-electron volt afterglow from a narrow jet in an extremely bright gamma-ray burst.

Some gamma-ray bursts (GRBs) have a tera-electron volt (TeV) afterglow, but the early onset of this has not been observed. We report observations with the Large High Altitude Air Shower Observatory (LHAASO) of the bright GRB 221009A, which serendipitously occurred within the instrument's field of view. More than 64,000 photons >0.2 TeV were detected within the first 3000 seconds. The TeV flux began several minutes after the GRB trigger and then rose to a peak ~10 seconds later. This was followed by a decay phase, which became more rapid ~650 seconds after the peak. We interpret the emission using a model of a relativistic jet with half-opening angle of ~0.8°. This is consistent with the core of a structured jet and could explain the high isotropic energy of this GRB.

Exploring Lorentz Invariance Violation from Ultrahigh-Energy γ Rays Observed by LHAASO.

Recently, the LHAASO Collaboration published the detection of 12 ultrahigh-energy γ-ray sources above 100 TeV, with the highest energy photon reaching 1.4 PeV. The first detection of PeV γ rays from astrophysical sources may provide a very sensitive probe of the effect of the Lorentz invariance violation (LIV), which results in decay of high-energy γ rays in the superluminal scenario and hence a sharp cutoff of the energy spectrum. Two highest energy sources are studied in this work. No signature of the existence of the LIV is found in their energy spectra, and the lower limits on the LIV energy scale are derived. Our results show that the first-order LIV energy scale should be higher than about 10^{5} times the Planck scale M_{Pl} and that the second-order LIV scale is >10^{-3}M_{Pl}. Both limits improve by at least one order of magnitude the previous results.

Constraints on Heavy Decaying Dark Matter from 570 Days of LHAASO Observations.

The kilometer square array (KM2A) of the large high altitude air shower observatory (LHAASO) aims at surveying the northern γ-ray sky at energies above 10 TeV with unprecedented sensitivity. γ-ray observations have long been one of the most powerful tools for dark matter searches, as, e.g., high-energy γ rays could be produced by the decays of heavy dark matter particles. In this Letter, we present the first dark matter analysis with LHAASO-KM2A, using the first 340 days of data from 1/2-KM2A and 230 days of data from 3/4-KM2A. Several regions of interest are used to search for a signal and account for the residual cosmic-ray background after γ/hadron separation. We find no excess of dark matter signals, and thus place some of the strongest γ-ray constraints on the lifetime of heavy dark matter particles with mass between 10^{5} and 10^{9} GeV. Our results with LHAASO are robust, and have important implications for dark matter interpretations of the diffuse astrophysical high-energy neutrino emission.

Peta-electron volt gamma-ray emission from the Crab Nebula.

The Crab Nebula is a bright source of gamma rays powered by the Crab Pulsar's rotational energy through the formation and termination of a relativistic electron-positron wind. We report the detection of gamma rays from this source with energies from 5 × 10-4 to 1.1 peta-electron volts with a spectrum showing gradual steepening over three energy decades. The ultrahigh-energy photons imply the presence of a peta-electron volt electron accelerator (a pevatron) in the nebula, with an acceleration rate exceeding 15% of the theoretical limit. We constrain the pevatron's size between 0.025 and 0.1 parsecs and the magnetic field to ≈110 microgauss. The production rate of peta-electron volt electrons, 2.5 × 1036 ergs per second, constitutes 0.5% of the pulsar spin-down luminosity, although we cannot exclude a contribution of peta-electron volt protons to the production of the highest-energy gamma rays.

Quantitative Analysis of Yeast Checkpoint Protein Kinase Activity by Combined Mass Spectrometry Enzyme Assays.

Virtually all eukaryotic cell functions and signaling pathways are regulated by protein phosphorylation. The Rad53 kinase plays crucial roles in the DNA damage response in Saccharomyces cerevisiae and is widely used as a surrogate marker for DNA damage checkpoint activation by diverse genotoxic agents. Most currently available assays for Rad53 activation are based on either electrophoretic mobility shifts or semiquantitative in situ autophosphorylation activity on protein blots. Here, we describe direct quantitative measures to assess Rad53 activity using immunoprecipitation kinase assays and quantitative mass spectrometric analysis of Rad53 activation loop autophosphorylation states. Both assays employ a highly specific Rad53 antibody, and thus enable the analysis of the untagged endogenous protein under physiological conditions. The principles of these assays are readily transferable to other protein kinases for which immunoprecipitation-grade antibodies are available, and thus potentially applicable to a wide range of eukaryotic signaling pathways beyond yeast.

A molecular model for neurodevelopmental disorders.

Genes implicated in neurodevelopmental disorders (NDDs) important in cognition and behavior may have convergent function and several cellular pathways have been implicated, including protein translational control, chromatin modification, and synapse assembly and maintenance. Here, we test the convergent effects of methyl-CpG binding domain 5 (MBD5) and special AT-rich binding protein 2 (SATB2) reduced dosage in human neural stem cells (NSCs), two genes implicated in 2q23.1 and 2q33.1 deletion syndromes, respectively, to develop a generalized model for NDDs. We used short hairpin RNA stably incorporated into healthy neural stem cells to supress MBD5 and SATB2 expression, and massively parallel RNA sequencing, DNA methylation sequencing and microRNA arrays to test the hypothesis that a primary etiology of NDDs is the disruption of the balance of NSC proliferation and differentiation. We show that reduced dosage of either gene leads to significant overlap of gene-expression patterns, microRNA patterns and DNA methylation states with control NSCs in a differentiating state, suggesting that a unifying feature of 2q23.1 and 2q33.1 deletion syndrome may be a lack of regulation between proliferation and differentiation in NSCs, as we observed previously for TCF4 and EHMT1 suppression following a similar experimental paradigm. We propose a model of NDDs whereby the balance of NSC proliferation and differentiation is affected, but where the molecules that drive this effect are largely specific to disease-causing genetic variation. NDDs are diverse, complex and unique, but the optimal balance of factors that determine when and where neural stem cells differentiate may be a major feature underlying the diverse phenotypic spectrum of NDDs.

*informatics: Identifying and Tracking Informatics Sub-Discipline Terms in the Literature.

OBJECTIVE: To identify the breadth of informatics sub-discipline terms used in the literature for enabling subsequent organization and searching by sub-discipline. METHODS: Titles in five literature sources were analyzed to extract terms for informatics sub-disciplines: 1) United States (U.S.) Library of Congress Online Catalog, 2) English Wikipedia, 3) U.S. National Library of Medicine (NLM) Catalog, 4) PubMed, and 5) PubMed Central. The extracted terms were combined and standardized with those in four vocabulary sources to create an integrated list: 1) Library of Congress Subject Headings (LCSH), 2) Medical Subject Headings (MeSH), 3) U.S. National Cancer Institute Thesaurus (NCIt), and 4) EMBRACE Data and Methods (EDAM). Searches for terms in titles from each literature source were conducted to obtain frequency counts and start years for characterizing established and potentially emerging sub-disciplines. RESULTS: Analysis of 6,949 titles from literature sources and 67 terms from vocabulary sources resulted in an integrated list of 382 terms for informatics sub-disciplines mapped to 292 preferred terms. In the last five decades, "bioinformatics", "medical informatics", "health informatics", "nursing informatics", and "biomedical informatics" were associated with the most literature. In the current decade, potentially emerging sub-disciplines include "disability informatics", "neonatal informatics", and "nanoinformatics" based on literature from the last five years. CONCLUSIONS: As the field of informatics continues to expand and advance, keeping up-to-date with historical and current trends will become increasingly challenging. The ability to track the accomplishments and evolution of a particular sub-discipline in the literature could be valuable for supporting informatics research, education, and training.

Association of APOA1 and APOA5 polymorphisms and haplotypes with lipid parameters in a Brazilian elderly cohort.

Apolipoproteins have an important role in lipid metabolism and transport. Polymorphisms in the APOA1/C3/A4/A5 gene cluster have been associated with lipid alterations and cardiovascular diseases. We investigated APOA1 XmnI, APOA5 S19W, and APOA5 -1131T>C polymorphisms in 377 individuals from a cohort of a longitudinal Brazilian elderly study. Allele frequencies, genotype distribution, and association with major morbidities as well as with lipids, creatinine, albumin, urea, glycated hemoglobin, and fasting glucose serum levels were investigated. Linkage disequilibrium and haplotype associations were also analyzed. This is the first time that haplotypes involving these polymorphisms were evaluated. Genotyping was performed by PCR-RFLP. Minor allele frequencies were 0.119, 0.071, and 0.158 for XmnI, S19W, and -1131T>C polymorphisms, respectively. We found a significant association of the -1131C allele with low LDL-C levels. We also observed that XmnI and S19W polymorphisms were in linkage disequilibrium. The C/G haplotype, which is composed of the wild-type allele of XmnI and the minor allele of S19W, was associated with high total cholesterol serum levels in this elderly population. We conclude that the -1131T>C polymorphism and the C/G haplotype, including XmnI and S19W polymorphisms, are associated with alterations in lipid levels and may be risk factors for cardiovascular disease in the Brazilian elderly.

Analysis of SNAP25 mRNA expression and promoter DNA methylation in brain areas of Alzheimer's Disease patients.

Alzheimer's Disease (AD) is the most common cause of dementia in elderly people. The presynaptic terminal is an important site of pathological changes in AD, leading to synaptic loss in specific brain regions, such as in the cortex and hippocampus. In this study, we investigated synaptosomal-associated protein, 25-kDa (SNAP25) mRNA levels and promoter DNA methylation in post mortem brain tissues (entorhinal and auditory cortices and hippocampus) from healthy elderly and AD subjects as well as in peripheral blood leukocytes of young, healthy elderly and AD patients. mRNA quantification was performed by quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) using the ΔΔC(T) method and promoter DNA methylation was quantified by mass spectrometry using the Sequenom EpiTYPER platform. We observed a significant decrease in SNAP25 expression in AD across all the three brain regions in relation to the healthy elderly subjects, suggesting impairment in synaptic function. The changes in the auditory cortex reflected those observed in the hippocampus and entorhinal cortex, the primary areas affected in AD. However, no AD-associated differences in SNAP25 promoter DNA methylation were observed suggesting that other mechanisms may be involved in mediating the observed gene expression changes.

Association of lipase lipoprotein polymorphisms with high-density lipoprotein and triglycerides in elderly men.

Lipoprotein lipase is essential for triglyceride hydrolysis. The polymorphisms S447X in exon 9 and HindIII in intron 8 have been associated with lower triglyceride levels and lower cardiovascular risk in adult men. We examined the association of these lipoprotein lipase polymorphisms with high-density lipoprotein (HDL) and triglyceride levels in elderly men. Blood samples were obtained from 87 elderly men, 48 of whom had cardiovascular disease and 39 (controls) had no history of cardiovascular events. The lipoprotein lipase polymorphisms were analyzed by PCR-RFLP. Allele frequencies were H- = 27.9% and X = 21.5%. There were no significant differences in allele frequencies or blood lipid levels between cardiovascular disease and control groups. However, the X allele was associated with a lower triglyceride/HDL ratio, 2.30 vs 3.02 for X allele absent (P = 0.03); the H-X haplotype was associated with lower triglyceride levels compared to the H+S haplotype (1.22 vs 1.58 mM, respectively) and a lower triglyceride/HDL ratio (2.29 vs 3.26, respectively). The X allele and H-X haplotype were associated with lower triglyceride/HDL ratios in these elderly men, independent of the history of cardiovascular events.

Association of lipase lipoprotein polymorphisms with high-density lipoprotein and triglycerides in elderly men.

Lipoprotein lipase is essential for triglyceride hydrolysis. The polymorphisms S447X in exon 9 and HindIII in intron 8 have been associated with lower triglyceride levels and lower cardiovascular risk in adult men. We examined the association of these lipoprotein lipase polymorphisms with high-density lipoprotein (HDL) and triglyceride levels in elderly men. Blood samples were obtained from 87 elderly men, 48 of whom had cardiovascular disease and 39 (controls) had no history of cardiovascular events. The lipoprotein lipase polymorphisms were analyzed by PCR-RFLP. Allele frequencies were H- = 27.9% and X = 21.5%. There were no significant differences in allele frequencies or blood lipid levels between cardiovascular disease and control groups. However, the X allele was associated with a lower triglyceride/HDL ratio, 2.30 vs 3.02 for X allele absent (P = 0.03); the H-X haplotype was associated with lower triglyceride levels compared to the H+S haplotype (1.22 vs 1.58 mM, respectively) and a lower triglyceride/HDL ratio (2.29 vs 3.26, respectively). The X allele and H-X haplotype were associated with lower triglyceride/HDL ratios in these elderly men, independent of the history of cardiovascular events.

TP53 codon 72 polymorphism as a risk factor for cardiovascular disease in a Brazilian population

TP53, a tumor suppressor gene, has a critical role in cell cycle, apoptosis and cell senescence and participates in many crucial physiological and pathological processes. Identification of TP53 polymorphism in older people and age-related diseases may provide an understanding of its physiology and pathophysiological role as well as risk factors for complex diseases. TP53 codon 72 (TP53:72) polymorphism was investigated in 383 individuals aged 66 to 97 years in a cohort from a Brazilian Elderly Longitudinal Study. We investigated allele frequency, genotype distribution and allele association with morbidities such as cardiovascular disease, type II diabetes, obesity, neoplasia, low cognitive level (dementia), and depression. We also determined the association of this polymorphism with serum lipid fractions and urea, creatinine, albumin, fasting glucose, and glycated hemoglobin levels. DNA was isolated from blood cells, amplified by PCR using sense 5'-TTGCCGTCCCAAGCAATGGATGA-3' and antisense 5'-TCTGGGAAGGGACAGAAGATGAC-3' primers and digested with the BstUI enzyme. This polymorphism is within exon 4 at nucleotide residue 347. Descriptive statistics, logistic regression analysis and Student t-test using the multiple comparison test were used. Allele frequencies, R (Arg) = 0.69 and P (Pro) = 0.31, were similar to other populations. Genotype distributions were within Hardy-Weinberg equilibrium. This polymorphism did not show significant association with any age-related disease or serum variables. However, R allele carriers showed lower HDL levels and a higher frequency of cardiovascular disease than P allele subjects. These findings may help to elucidate the physiopathological role of TP53:72 polymorphism in Brazilian elderly people.

TP53 codon 72 polymorphism as a risk factor for cardiovascular disease in a Brazilian population.

TP53, a tumor suppressor gene, has a critical role in cell cycle, apoptosis and cell senescence and participates in many crucial physiological and pathological processes. Identification of TP53 polymorphism in older people and age-related diseases may provide an understanding of its physiology and pathophysiological role as well as risk factors for complex diseases. TP53 codon 72 (TP53:72) polymorphism was investigated in 383 individuals aged 66 to 97 years in a cohort from a Brazilian Elderly Longitudinal Study. We investigated allele frequency, genotype distribution and allele association with morbidities such as cardiovascular disease, type II diabetes, obesity, neoplasia, low cognitive level (dementia), and depression. We also determined the association of this polymorphism with serum lipid fractions and urea, creatinine, albumin, fasting glucose, and glycated hemoglobin levels. DNA was isolated from blood cells, amplified by PCR using sense 5'-TTGCCGTCCCAAGCAATGGATGA-3' and antisense 5'-TCTGGGAAGGGACAGAAGATGAC-3' primers and digested with the BstUI enzyme. This polymorphism is within exon 4 at nucleotide residue 347. Descriptive statistics, logistic regression analysis and Student t-test using the multiple comparison test were used. Allele frequencies, R (Arg) = 0.69 and P (Pro) = 0.31, were similar to other populations. Genotype distributions were within Hardy-Weinberg equilibrium. This polymorphism did not show significant association with any age-related disease or serum variables. However, R allele carriers showed lower HDL levels and a higher frequency of cardiovascular disease than P allele subjects. These findings may help to elucidate the physiopathological role of TP53:72 polymorphism in Brazilian elderly people.

Molecular electron affinities and the calculation of the temperature dependence of the electron-capture detector response.

The use of the electron-capture detector (ECD) to measure molecular electron affinities and kinetic parameters for reactions of thermal electrons is reviewed. The advances of the past decade are emphasized and include the multistate electron-capture detector model and the use of semi-empirical self-consistent field quantum mechanical calculations and half wave reduction potential values to support gas phase experimental results. A procedure for the evaluation of the adiabatic electron affinities of the main group elements and the homonuclear diatomic molecules is presented. Potential excited states are identified for the magnetron (MGN) values for quinones, thermal charge transfer (TCT) values for CS2, C6F6, SF6 and photoelectron spectroscopy (PES) values for O2, NO, nitromethane, and the nucleic acids. Literature electron affinities are then evaluated. The temperature dependence of the electron-capture detector can be calculated using values for kinetic rate constants and electron affinities to optimize response and temperature sensitivity in analytical procedures. The temperature dependence for adenine, guanine, thymine and cytosine are predicted for reactions with thermal electrons. Using the recent advances, the new adiabatic electron affinities are: all in electron volts (eV), 4-F-benzaldehyde (0.57 +/- 0.05) and acetophenones (APs) 4-F-AP (0.52 +/- 0.05); 2-CF3-AP (0.79 +/- 0.05); 3-CF3-AP (0.79 +/- 0.05); 4-CF3-AP (0.89 +/- 0.05); 3-CI-AP (0.67 +/- 0.05); and 4-Cl-AP (0.64 +/- 0.05). The adiabatic electron affinities of chloro and fluorobenzenes range from 0.17 to 1.15 eV and 0.13 to 0.86 eV.

The negative ion states of molecules: adenine and guanine.

Anions of cytosine and thymine predominate in radiation-damaged DNA. This is in contrast to the experimental order of adiabatic electron affinities: A, 0.95; G, 1.51; >T, 0.79, U, 0.80; C, 0.56 (+/-0.05 eV). Excited negative-ion states of adenine (A) and guanine (G) are identified using semiempirical AM1-MCCI quantum mechanical calculations. A planar G(-) has an excited state adiabatic electron affinity, AEA*, of 0.3 +/- 0.05 eV. This state and the unique Watson-Crick structure are responsible for the preponderance of charge on C(-) in radiation-damaged DNA. By analogy to the value for cytosine, the dipole-bound EA of G is estimated as 0.25 eV. New AEA values from literature reduction potentials for the ribose nucleotides are rC, 0.6; rU, 0.8; and rT, 0.8 (+/-0.1 eV). From literature photoelectron spectroscopy, AEA* vales for U are 0.15, 0.3, 0.5, and 0.6 eV. In GC(-2), stacked [GC:GC](-3), and [GC:GC:GC](-4), the charge moves to G. In [GC:GC:GC](-2 to -4), the charge moves from GC(1) to GC(3) through space without a bridge or bond. This is important to electron conduction, radiation damage and repair, and nanoscale devices.

Attenuation of lung inflammation and fibrosis in interferon-gamma-deficient mice after intratracheal bleomycin.

Because mouse strains susceptible to bleomycin, such as C57BL/ 6J, tend to produce T helper type 1 (Th1) cytokines in response to immune activation, we hypothesized that the inflammatory response to bleomycin is mediated, in part, by local production of the Th1 cytokine interferon-gamma (IFN-gamma). Consistent with this hypothesis, fibrosis-prone C57BL/6J and A/J mice demonstrated significantly elevated expression of IFN-gamma protein (by enzyme-linked immunosorbent assay) in bronchoalveolar lavage fluid at 24 h, and subsequently increased lung inflammation, weight loss, and mortality 10 d after intratracheal bleomycin administration compared with fibrosis-resistant BALB/c mice or saline control mice. To directly determine a role for IFN-gamma in bleomycin toxicity, we exposed C57BL/6J mice with a homozygous null mutation of the IFN-gamma gene (IFN-gamma[-/-]) and wild-type C57BL/6J mice to intratracheal bleomycin. IFN-gamma(-/-) mice demonstrated significantly lower parenchymal inflammation, weight loss, and mortality 10 d after 5 U/kg intratracheal bleomycin administration compared with control mice. At 3 wk after 1.5 U/kg bleomycin exposure, single lung collagen determined by hydroxyproline assay was significantly lower in IFN-gamma(-/-) mice compared with wild-type C57BL/6J mice. Together, these results suggest that IFN-gamma mediates, in part, bleomycin-induced pulmonary inflammation and fibrosis.