A Note on Temperature and Energy of 4-dimensional Black Holes from Entropic Force

We investigate the temperature and energy on holographic screens for 4-dimensional black holes with the entropic force idea proposed by Verlinde. We find that the "Unruh-Verlinde temperature" is equal to the Hawking temperature on the horizon and can be considered as a generalized Hawking temperature on the holographic screen outside the horizons. The energy on the holographic screen is not the black hole mass $M$ but the reduced mass $M_0$, which is related to the black hole parameters. With the replacement of the black hole mass $M$ by the reduced mass $M_0$, the entropic force can be written as $F=\frac{GmM_0}{r^2}$, which could be tested by experiments.Comment: V4: 13 pages, 4 figures, title changed, discussions for experiments added, accepted by CQ

Synthesis of Mesoporous Silica@Co–Al Layered Double Hydroxide Spheres: Layer-by-Layer Method and Their Effects on the Flame Retardancy of Epoxy Resins

Hierarchical mesoporous silica@Co–Al layered double hydroxide (m-SiO2@Co–Al LDH) spheres were prepared through a layer-by-layer assembly process, in order to integrate their excellent physical and chemical functionalities. TEM results depicted that, due to the electrostatic potential difference between m-SiO2 and Co–Al LDH, the synthetic m-SiO2@Co–Al LDH hybrids exhibited that m-SiO2 spheres were packaged by the Co–Al LDH nanosheets. Subsequently, the m-SiO2@Co–Al LDH spheres were incorporated into epoxy resin (EP) to prepare specimens for investigation of their flame-retardant performance. Cone results indicated that m-SiO2@Co–Al LDH incorporated obviously improved fire retardant of EP. A plausible mechanism of fire retardant was hypothesized based on the analyses of thermal conductivity, char residues, and pyrolysis fragments. Labyrinth effect of m-SiO2 and formation of graphitized carbon char catalyzed by Co–Al LDH play pivotal roles in the flame retardance enhancement

Does or did the supernova remnant Cassiopeia A operate as a PeVatron?

For decades, supernova remnants (SNRs) have been considered the prime sources of Galactic Cosmic rays (CRs). But whether SNRs can accelerate CR protons to PeV energies and thus dominate CR flux up to the knee is currently under intensive theoretical and phenomenological debate. The direct test of the ability of SNRs to operate as CR PeVatrons can be provided by ultrahigh-energy (UHE; $E_\gamma \geq 100$~TeV) $\gamma$-rays. In this context, the historical SNR Cassiopeia A (Cas A) is considered one of the most promising target for UHE observations. This paper presents the observation of Cas A and its vicinity by the LHAASO KM2A detector. The exceptional sensitivity of LHAASO KM2A in the UHE band, combined with the young age of Cas A, enabled us to derive stringent model-independent limits on the energy budget of UHE protons and nuclei accelerated by Cas A at any epoch after the explosion. The results challenge the prevailing paradigm that Cas A-type SNRs are major suppliers of PeV CRs in the Milky Way.Comment: 11 pages, 3 figures, Accepted by the APJ

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 $\gamma$-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 work we report the measurements of diffuse $\gamma$-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 ($15^{\circ}<l<125^{\circ}$, $|b|<5^{\circ}$) and outer ($125^{\circ}<l<235^{\circ}$, $|b|<5^{\circ}$) Galactic plane are detected with $29.1\sigma$ and $12.7\sigma$ significance, respectively. The outer Galactic plane diffuse emission is detected for the first time in the very- to ultra-high-energy domain ($E>10$~TeV). The energy spectrum in the inner Galaxy regions can be described by a power-law function with an index of $-2.99\pm0.04$, 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 $\sim3$ than the prediction. A similar spectrum with an index of $-2.99\pm0.07$ is found in the outer Galaxy region, and the absolute flux for $10\lesssim E\lesssim60$ 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.Comment: 12 pages, 8 figures, 5 tables; accepted for publication in Physical Review Letters; source mask file provided as ancillary fil

The Biomolecular Interaction Network Database and related tools 2005 update

The Biomolecular Interaction Network Database (BIND) (http://bind.ca) archives biomolecular interaction, reaction, complex and pathway information. Our aim is to curate the details about molecular interactions that arise from published experimental research and to provide this information, as well as tools to enable data analysis, freely to researchers worldwide. BIND data are curated into a comprehensive machine-readable archive of computable information and provides users with methods to discover interactions and molecular mechanisms. BIND has worked to develop new methods for visualization that amplify the underlying annotation of genes and proteins to facilitate the study of molecular interaction networks. BIND has maintained an open database policy since its inception in 1999. Data growth has proceeded at a tremendous rate, approaching over 100 000 records. New services provided include a new BIND Query and Submission interface, a Standard Object Access Protocol service and the Small Molecule Interaction Database (http://smid.blueprint.org) that allows users to determine probable small molecule binding sites of new sequences and examine conserved binding residues

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-β protein (Aβ), intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated microtubule-associated protein tau (MAP-tau), and microtubule destabilization. Early-onset autosomal dominant AD genes are associated with excessive Aβ accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking Aβ and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by Aβ-amyloid deposits (Aβ oligomers and plaques) not only drives Aβ aggregation, but also disrupts zinc homeostasis in zinc-enriched brain regions important for memory and vulnerable to AD pathology, resulting in intra-neuronal zinc levels, which are either too low, or excessively high. To evaluate this hypothesis, we 1) used molecular modeling of zinc binding to the microtubule component protein tubulin, identifying specific, high-affinity zinc binding sites that influence side-to-side tubulin interaction, the sensitive link in microtubule polymerization and stability. We also 2) performed kinetic modeling showing zinc distribution in extra-neuronal Aβ deposits can reduce intra-neuronal zinc binding to microtubules, destabilizing microtubules. Finally, we 3) used metallomic imaging mass spectrometry (MIMS) to show anatomically-localized and age-dependent zinc dyshomeostasis in specific brain regions of Tg2576 transgenic, mice, a model for AD. We found excess zinc in brain regions associated with memory processing and NFT pathology. Overall, we present a theoretical framework and support for a new theory of AD linking extra-neuronal Aβ amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on β-amyloid-induced alterations in zinc ion concentration inside neurons affecting stability of polymerized microtubules, their binding to MAP-tau, and molecular dynamics involved in cognition. Further, our theory supports novel AD therapeutic strategies targeting intra-neuronal zinc homeostasis and microtubule dynamics to prevent neurodegeneration and cognitive decline

Variation in the Glucose Transporter gene <i>SLC2A2 </i>is associated with glycaemic response to metformin

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear1. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10−14) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine